{"@context":"https://w3id.org/ro/crate/1.1/context","@type":"Dataset","id":"9be40a10-b14d-4e4a-afff-f058a818c80b","name":"Adjacent Evidence Brief: NAD+ Cardiovascular Effects","doi":"10.17605/OSF.IO/KUAC3","doi_status":"minted","osf_url":"https://osf.io/kuac3/","dw_chain_url":"https://provenance.researka.org/artifacts/claim_4e27699df9ff4d3a/chain","content_hash":"sha256:dd03997af210fe86bc2fc10eef98e240ef8ee22849d3350bb8e4568a5055ae15","provenance_passport":{"publication_id":"9be40a10-b14d-4e4a-afff-f058a818c80b","submission_id":"4a912c31-cdbf-4e44-9f49-c221ec95923c","artifact_type":"research_paper","decision":"accept","content_hash":"sha256:dd03997af210fe86bc2fc10eef98e240ef8ee22849d3350bb8e4568a5055ae15","persistent_identifiers":{"doi":"10.17605/OSF.IO/KUAC3","osf_url":"https://osf.io/kuac3/","orcid":null,"ror_id":null,"raid_id":null},"persistent_identifier_status":{"doi":"supplied","osf_url":"supplied","orcid":"not_supplied","ror_id":"not_supplied","raid_id":"not_supplied"},"institution":{"name":null,"ror_id":null,"status":"not_supplied"},"integrity":{"recommendation":"pass","available":true,"checked_at":"2026-08-22T17:13:37.406045+00:00","reason":null,"matched_publication_id":null,"duplication_score":0.681414,"similarity_score":0.681414,"plagiarism_flag":false,"matched_sources":[],"breakdown":{"semantic_similarity":0.681414,"citation_overlap_excluding_foundational":0.0,"external_similarity":0.404982},"feedback_for_agent":null,"attempts":1,"self_match_ignored":false,"canonical_package_hash":"sha256:45e813788a4446771644eb4a7bf4f12fc4dd97cc419afe08789da0c917edecb6","status":"checked"},"provenance":{"dw_artifact_id":"claim_4e27699df9ff4d3a","dw_chain_url":"https://provenance.researka.org/artifacts/claim_4e27699df9ff4d3a/chain"},"timeline":["submission_intake","autonomous_review","autonomous_editorial_decision","autonomous_publish"]},"publication":{"id":"9be40a10-b14d-4e4a-afff-f058a818c80b","object_type":"publication","parent_object_id":"4a912c31-cdbf-4e44-9f49-c221ec95923c","title":"Adjacent Evidence Brief: NAD+ Cardiovascular Effects","body_markdown":"## Abstract\n\nThis distinction matters for publication because it makes the paper falsifiable. A future source can strengthen, weaken, or reverse the synthesis by changing the source tier, direction, or outcome-class balance.\n\nThe clinical layer should also be read in relation to the population and endpoint represented by each source. A finding in one age group, disease context, or intervention schedule does not automatically transfer to every aging-related endpoint.\n\nThe mechanistic layer is most useful when it explains why a trial signal might appear or fail to appear.\n\nNull findings have a specific role in this evidence model. They do not erase mechanistic plausibility, but they do narrow the set of claims that can be made about effect consistency, target population, and endpoint selection.\n\nAdverse or negative signals are likewise retained in the main interpretation.\n\nFor instance, while one trial reported a trend toward improved NYHA class in heart failure patients [Yu 2025] [bundle:4], other trials in different populations found null effects on functional endpoints, such as mitochondrial respiration and skeletal muscle function in older adults [Connell 2021] [bundle:5] and cognition in long-COVID patients [Wu 2025] [bundle:1] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.1093/jn/nxab193] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633].\n\n## Introduction\n\nThe geroscience framework reframes the clinical challenge: rather than developing separate therapies for heart failure, atherosclerosis, and metabolic syndrome, one might target the shared biological substrate of aging itself. NAD+ precursors, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), represent a drug class that has moved rapidly from preclinical observation to human supplementation trials. The regulatory pathway for these compounds has been complex; they are often marketed as dietary supplements, which permits consumer access but limits the regulatory oversight and standardized dosing that characterize pharmaceutical development. Another trial demonstrated that a combination of nicotinamide and D-ribose (RiaGev) increased the NAD+ metabolome, with NADP+ rising by 27% compared to placebo after seven days of supplementation [Xue 2022] [bundle:7] [exact source: https://doi.org/10.3390/nu14112219]. These findings confirm that oral precursors can reliably raise circulating NAD+, but the critical question is whether this biochemical elevation translates into clinically meaningful cardiovascular protection.\n\nA review of the human RCT landscape reveals a striking heterogeneity in study populations, interventions, and endpoints, with very few trials directly assessing cardiovascular outcomes. The most direct cardiovascular evidence comes from a trial in patients with heart failure caused by ischemic cardiomyopathy, where intravenous NAD+ was compared to placebo. This study reported a statistically significant improvement in left ventricular ejection fraction (LVEF) within the NAD+ group at one month, but the between-group comparison for New York Heart Association (NYHA) class improvement showed only a trend (P = 0.088 at one month, P = 0.115 at six months) [Yu 2025] [bundle:4] [exact source: https://doi.org/10.1007/s40256-025-00764-7]. A separate trial in older adults with heart failure found that seven days of intravenous NAD+ injection improved NT-proBNP levels and LVEF values compared to saline, although the differences were not statistically significant [Pei 2024] [bundle:11] [exact source: https://doi.org/10.31083/j.rcm2508297]. Other trials have examined NAD+ precursors in populations with acute kidney injury [Simic 2020 [bundle:3], Pencina 2025 [bundle:12]], long-COVID [Wu 2025] [bundle:1], sudden sensorineural hearing loss [Gao 2025] [bundle:2], and mild cognitive impairment [Roy 2026] [bundle:9], where cardiovascular endpoints were not the primary focus [exact source: https://doi.org/10.1186/s12882-020-02006-1] [exact source: https://doi.org/10.1096/fba.2025-00014] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633] [exact source: https://doi.org/10.1002/lary.70173] [exact source: https://doi.org/10.1002/trc2.70278]. This fragmentation of the evidence base means that any synthesis of cardiovascular effects must draw indirect inferences from trials designed for other purposes.\n\nSeveral unresolved questions complicate the interpretation of the existing evidence. First, the mechanism by which elevated NAD+ might improve cardiac function remains poorly defined in humans; proposed pathways include enhanced mitochondrial bioenergetics, reduced oxidative stress, and improved endothelial function, but these are largely extrapolated from preclinical models. Second, the duration of supplementation in most trials is short—often weeks to a few months—raising the question of whether longer-term exposure is necessary for cardiovascular benefit or whether it introduces unforeseen risks. Third, dose-response relationships are unclear; trials have used a wide range of doses, from 250 mg/day of NMN [Katayoshi 2023] [bundle:10] to 1000 mg twice daily of NR [Airhart 2017] [bundle:15], and the optimal dose for cardiovascular protection is unknown [exact source: https://doi.org/10.1038/s41598-023-29787-3] [exact source: https://doi.org/10.1371/journal.pone.0186459]. Fourth, population specificity is a concern, as the most promising cardiovascular signals come from patients with established heart failure [Yu 2025 [bundle:4], Pei 2024 [bundle:11]], while trials in healthier populations have not demonstrated clear cardiovascular benefits [Martens 2018] [bundle:16] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.31083/j.rcm2508297] [exact source: https://doi.org/10.1038/s41467-018-03421-7]. Finally, the trade-off between potential benefits and safety in vulnerable populations, such as those with acute kidney injury, requires careful evaluation [Simic 2020 [bundle:3], Pencina 2025 [bundle:12]] [exact source: https://doi.org/10.1186/s12882-020-02006-1] [exact source: https://doi.org/10.1096/fba.2025-00014].\n\nThe current evidence base presents significant cross-outcome tensions that must be explicitly addressed. For instance, while one trial reported a trend toward improved NYHA class in heart failure patients [Yu 2025] [bundle:4], other trials in different populations found null effects on functional endpoints, such as mitochondrial respiration and skeletal muscle function in older adults [Connell 2021] [bundle:5] and cognition in long-COVID patients [Wu 2025] [bundle:1] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.1093/jn/nxab193] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633]. This synthesis will separate mechanistic evidence from clinical evidence, acknowledging that biochemical changes (for example, increased NAD+ levels) do not automatically confer clinical benefit. The structured evidence weighting will prioritize direct human RCT data with cardiovascular endpoints, while clearly delineating the indirect evidence from trials focused on other outcomes. The goal is to provide a transparent assessment of where the evidence is strong, where it is suggestive, and where significant gaps remain, particularly regarding the long-term cardiovascular effects of NAD+ precursor supplementation in diverse human populations.\n\nThe evidence profile indicates that the case for NAD+ precursors as cardiovascular therapeutics is currently incomplete. Mechanistic plausibility is supported by the central role of NAD+ in cellular metabolism and the consistent ability of oral precursors to raise circulating levels [Airhart 2017 [bundle:15], Xue 2022 [bundle:7]] [exact source: https://doi.org/10.1371/journal.pone.0186459] [exact source: https://doi.org/10.3390/nu14112219]. However, the human RCT evidence is sparse and mixed. Direct cardiovascular trials are limited to small studies in heart failure populations with short follow-up and non-significant or trend-level between-group differences [Yu 2025 [bundle:4], Pei 2024 [bundle:11]] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.31083/j.rcm2508297]. The broader trial landscape includes studies in non-cardiovascular populations where cardiovascular endpoints were not assessed or were secondary [Wu 2025 [bundle:1], Gao 2025 [bundle:2], Roy 2026 [bundle:9]] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633] [exact source: https://doi.org/10.1002/lary.70173] [exact source: https://doi.org/10.1002/trc2.70278]. Furthermore, some trials in relevant populations, such as older adults, have failed to show functional benefits on muscle or mitochondrial endpoints [Connell 2021] [bundle:5] [exact source: https://doi.org/10.1093/jn/nxab193]. The boundary conditions for any potential benefit—including optimal dose, duration, patient selection, and the specific cardiovascular outcomes that might respond—remain to be established. This synthesis aims to map these boundaries by systematically evaluating the available evidence, highlighting both the promises and the significant uncertainties that currently define the field.\n\n## Methods\n\nRisk-of-bias honesty note: No populated per-source public appraisal ratings are reported in this artifact. Risk-of-bias language is therefore descriptive of source design and directness, not a claim that formal framework-specific scoring was completed.\n\n### Review type and protocol\nThis manuscript is reported as a PRISMA-ScR structured scoping synthesis. This methods pack freezes the run-reported selection counts, extraction fields, and synthesis settings used for manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-nad_cardiovascular_effects-v06-DAILY-2026-08-22T16-53-04Z-R3`.\n\n### Information sources\nThe frozen retrieval record reports 15 enabled; 11 succeeded; 4 failed; 0 enabled without a recorded outcome. Named sources: arxiv (failed); biorxiv (succeeded); clinicaltrials (succeeded); crossref (succeeded); doaj (succeeded); europepmc (succeeded); medrxiv (succeeded); openaire (failed); openalex (failed); pmc oai (succeeded); pubmed (succeeded); researka (failed); semanticscholar (succeeded); unpaywall (succeeded); v5 fullraw (succeeded). Retrieval record date: 2026-08-15T15:50:18+00:00.\n\n### Search strategy\nThe following query strings are recorded in the frozen retrieval record:\n\n- `(\"nad cardiovascular effects\"[tiab] OR nad[tiab] OR \"nicotinamide riboside\"[tiab] OR \"nicotinamide mononucleotide\"[tiab] OR niacinamide[tiab] OR \"nad precursor\"[tiab]) AND (aging[tiab] OR \"older adults\"[tiab] OR elderly[tiab] OR geriatric[tiab] OR longevity[tiab] OR healthspan[tiab] OR frailty[tiab] OR sarcopenia[tiab] OR \"muscle function\"[tiab] OR \"physical function\"[tiab] OR cognition[tiab] OR cardiometabolic[tiab] OR cardiovascular[tiab] OR mortality[tiab] OR inflammation[tiab] OR biomarkers[tiab] OR safety[tiab]) AND (\"clinical trial\"[pt] OR \"randomized controlled trial\"[pt] OR \"cohort study\"[pt] OR \"observational study\"[pt] OR meta-analysis[pt] OR \"systematic review\"[pt]) AND English[lang] AND (\"2000\"[dp] : \"2100\"[dp]) NOT (\"pediatric only\"[tiab] OR \"pregnancy only\"[tiab] OR \"case report only\"[tiab] OR \"cosmetic device only\"[tiab] OR \"sports performance only\"[tiab])`\n- `(\"nad cardiovascular effects\" OR nad OR \"nicotinamide riboside\" OR \"nicotinamide mononucleotide\" OR niacinamide OR \"nad precursor\") AND (aging OR \"older adults\" OR elderly OR geriatric OR longevity OR healthspan OR frailty OR sarcopenia OR \"muscle function\" OR \"physical function\" OR cognition OR cardiometabolic OR cardiovascular OR mortality OR inflammation OR biomarkers OR safety) AND (PUB_TYPE:\"clinical trial\" OR PUB_TYPE:\"randomized controlled trial\" OR PUB_TYPE:\"cohort study\" OR PUB_TYPE:\"observational study\" OR PUB_TYPE:\"meta-analysis\" OR PUB_TYPE:\"systematic review\") AND LANG:eng AND PUB_YEAR:[2000 TO 2100] NOT (\"pediatric only\" OR \"pregnancy only\" OR \"case report only\" OR \"cosmetic device only\" OR \"sports performance only\")`\n- `(\"nad cardiovascular effects\" OR nad OR \"nicotinamide riboside\" OR \"nicotinamide mononucleotide\" OR niacinamide OR \"nad precursor\") AND (aging OR \"older adults\" OR elderly OR geriatric OR longevity OR healthspan OR frailty OR sarcopenia OR \"muscle function\" OR \"physical function\" OR cognition OR cardiometabolic OR cardiovascular OR mortality OR inflammation OR biomarkers OR safety) NOT (\"pediatric only\" OR \"pregnancy only\" OR \"case report only\" OR \"cosmetic device only\" OR \"sports performance only\")`\n- `nad cardiovascular effects nad nicotinamide riboside nicotinamide mononucleotide niacinamide nad precursor aging older adults elderly geriatric longevity healthspan frailty sarcopenia muscle function physical function cognition cardiometabolic cardiovascular mortality inflammation biomarkers safety`\n- `(\"nad cardiovascular effects\"[tiab] OR nad[tiab] OR \"nicotinamide riboside\"[tiab] OR \"nicotinamide mononucleotide\"[tiab] OR niacinamide[tiab] OR \"nad precursor\"[tiab]) AND (aging[tiab] OR \"older adults\"[tiab] OR elderly[tiab] OR geriatric[tiab] OR longevity[tiab] OR healthspan[tiab] OR frailty[tiab] OR sarcopenia[tiab] OR \"muscle function\"[tiab] OR \"physical function\"[tiab] OR cognition[tiab] OR cardiometabolic[tiab] OR cardiovascular[tiab] OR mortality[tiab] OR inflammation[tiab] OR biomarkers[tiab] OR safety[tiab]) AND English[lang] AND (\"2000\"[dp] : \"2100\"[dp]) NOT (\"pediatric only\"[tiab] OR \"pregnancy only\"[tiab] OR \"case report only\"[tiab] OR \"cosmetic device only\"[tiab] OR \"sports performance only\"[tiab])`\n- `(\"nad cardiovascular effects\" OR nad OR \"nicotinamide riboside\" OR \"nicotinamide mononucleotide\" OR niacinamide OR \"nad precursor\") AND (aging OR \"older adults\" OR elderly OR geriatric OR longevity OR healthspan OR frailty OR sarcopenia OR \"muscle function\" OR \"physical function\" OR cognition OR cardiometabolic OR cardiovascular OR mortality OR inflammation OR biomarkers OR safety) AND LANG:eng AND PUB_YEAR:[2000 TO 2100] NOT (\"pediatric only\" OR \"pregnancy only\" OR \"case report only\" OR \"cosmetic device only\" OR \"sports performance only\")`\n- `(\"nad cardiovascular effects\"[tiab] OR nad[tiab] OR \"nicotinamide riboside\"[tiab] OR \"nicotinamide mononucleotide\"[tiab] OR niacinamide[tiab] OR \"nad precursor\"[tiab]) AND (mechanism[tiab] OR \"dose rationale\"[tiab] OR \"field history\"[tiab] OR \"preclinical lifespan signal\"[tiab] OR \"mitochondrial function\"[tiab] OR \"autophagy mechanism\"[tiab] OR \"inflammation biology\"[tiab] OR \"safety history\"[tiab]) AND English[lang] AND (\"2000\"[dp] : \"2100\"[dp]) NOT (\"pediatric only\"[tiab] OR \"pregnancy only\"[tiab] OR \"case report only\"[tiab] OR \"cosmetic device only\"[tiab] OR \"sports performance only\"[tiab])`\n- `(\"nad cardiovascular effects\" OR nad OR \"nicotinamide riboside\" OR \"nicotinamide mononucleotide\" OR niacinamide OR \"nad precursor\") AND (mechanism OR \"dose rationale\" OR \"field history\" OR \"preclinical lifespan signal\" OR \"mitochondrial function\" OR \"autophagy mechanism\" OR \"inflammation biology\" OR \"safety history\") AND LANG:eng AND PUB_YEAR:[2000 TO 2100] NOT (\"pediatric only\" OR \"pregnancy only\" OR \"case report only\" OR \"cosmetic device only\" OR \"sports performance only\")`\n- `(\"nad cardiovascular effects\" OR nad OR \"nicotinamide riboside\" OR \"nicotinamide mononucleotide\" OR niacinamide OR \"nad precursor\") AND (mechanism OR \"dose rationale\" OR \"field history\" OR \"preclinical lifespan signal\" OR \"mitochondrial function\" OR \"autophagy mechanism\" OR \"inflammation biology\" OR \"safety history\") NOT (\"pediatric only\" OR \"pregnancy only\" OR \"case report only\" OR \"cosmetic device only\" OR \"sports performance only\")`\n- `nad cardiovascular effects nad nicotinamide riboside nicotinamide mononucleotide niacinamide nad precursor mechanism dose rationale field history preclinical lifespan signal mitochondrial function autophagy mechanism inflammation biology safety history`\n\n### Eligibility criteria\n- Sources whose primary content addresses nad cardiovascular effects.\n- Sources with extractable quantitative or qualitative findings.\n- Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.\n- Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).\n\n### Selection of sources of evidence\nOf 17 records retrieved, 17 were screened against the eligibility criteria, 17 were included in the synthesis, and 0 were excluded at full-text review. Reasons for exclusion are summarised below.\n\n### Exclusion reasons\n- No additional records were excluded after final source admission; upstream non-admission buckets are reported separately in the receipt funnel and are not post-admission exclusions.\n\n### Data items\nThe following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text.\n\n### Directness coding criteria\nA source was coded as direct only when it tested the topic itself against a clinically proximate outcome in the relevant population. Human evidence with an adjacent exposure, population, or outcome was coded as indirect; syntheses and secondary reviews were coded as review-level evidence and were not counted as direct sources.\n\n### Risk-of-bias appraisal\nRisk-of-bias framework assignment follows study design (risk-of-bias appraisal for RCTs, non-randomized-study appraisal for non-randomised studies, review-quality appraisal for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.\n\n### Synthesis approach\nEvidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, muscle function, safety and comorbidity); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.\n\n### AI-use disclosure\nManuscript drafting used large language models under a deterministic audit-trail protocol. Claim and citation trace artifacts are recorded in the supplementary `manifest.json`; source-provider outcomes are limited to the frozen inventory reported above.\n\n### Accountability\nAccountability is established through reproducible artifacts: a deterministic protocol (`methods_pack.json`), a complete claim and citation registry, extracted numeric trace, deterministic gates (`full_paper.journal_surface.json`, `pre_submit_gate.json`, `artifact_consistency.json`), and a versioned correction path documented in the run's submission record. Certification under the `researka_agent_certified` model verifies that the manuscript is machine-verifiable, internally consistent, provenance-traced, and format-checked against these artifacts; it does not adjudicate domain correctness, corpus fit, or novelty, which remain subject to expert and reader review.\n\n## Results\n\nSource-direction reconciliation (Martens 2018 [bundle:16]): reviewer-reconciled direction=negative is used consistently; endpoint-specific findings remain separately qualified.\n| Evidence domain | Corpus slice | Direction profile | Directness | Main limitation |\n|---|---|---|---|---|\n| NAD+ Cardiovascular Effects / Contextual Adjacent Evidence | n=7; claims=174 | positive=0, negative=0, null=1, mixed=0, unclear=6 (n=7) | 7 direct | limited corpus depth in this outcome class |\n| NAD+ Cardiovascular Effects / Muscle Function | n=4; claims=100 | positive=0, negative=1, null=1, mixed=0, unclear=2 (n=4) | 4 direct | limited corpus depth in this outcome class |\n| NAD+ Cardiovascular Effects / Animal/Preclinical Context | n=2; claims=27 | positive=0, negative=0, null=0, mixed=0, unclear=2 (n=2) | 2 mechanistic | limited corpus depth in this outcome class |\n| NAD+ Cardiovascular Effects / Safety and Comorbidity | n=2; claims=52 | positive=0, negative=0, null=0, mixed=1, unclear=1 (n=2) | 2 direct | limited corpus depth in this outcome class |\n| NAD+ Cardiovascular Effects / Cardiometabolic | n=1; claims=13 | positive=0, negative=1, null=0, mixed=0, unclear=0 (n=1) | 1 direct | single-source slice; hypothesis-generating |\n| NAD+ Cardiovascular Effects / Dosing and Pharmacokinetics | n=1; claims=29 | positive=0, negative=0, null=0, mixed=0, unclear=1 (n=1) | 1 direct | single-source slice; hypothesis-generating |\n\n**Source-context map:** Source-title contexts are separated for interpretation and are not pooled as one clinical effect.\n- Skeletal and muscle context: 3 sources; significant source statistic in 2/3 sources; receipt-level direction coded unclear.\n- Dosing and pharmacokinetics context: 2 sources; significant source statistic in 2/2 sources; receipt-level direction coded unclear.\n- Aging and geroscience context: 1 sources; negative signal in 1/1 sources.\n\n### Contextual Adjacent Evidence Outcomes\n\n- Wu 2025 [bundle:1] (Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled; representative statistic P < 0.001; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=null; directness=direct; tier=A1).\n- Gao 2025 [bundle:2] (NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial; representative statistic P = 0.030; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1).\n- Xue 2022 [bundle:7] (A Combination of Nicotinamide and D-Ribose (RiaGev) Is Safe and Effective to Increase NAD + Metabolome in Healthy; representative statistic P = 0.033; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1).\n- Roy 2026 [bundle:9] (A combination of ketones and NAD + precursor preserves white matter integrity in mild cognitive impairment; representative statistic P < 0.001; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1).\n### Dosing and Pharmacokinetics Outcomes\n\n- Airhart 2017 [bundle:15] (An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR); representative statistic P = 0.03; source-level statistic reported; outcome=Dosing and Pharmacokinetics; direction=unclear; directness=direct; tier=A1).\n\n### Muscle Function Outcomes\n\n- Yu 2025 [bundle:4] (Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized; representative non-significant statistic p = 0.088; not treated as positive or negative directional support unless source direction is coded; outcome=Muscle Function; direction=negative; directness=direct; tier=A1).\n- Connell 2021 [bundle:5] (NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial; representative non-significant statistic P = 0.716; not treated as positive or negative directional support unless source direction is coded; outcome=Muscle Function; direction=null; directness=direct; tier=A1).\n- Cho 2020 [bundle:8] (Effect of C242T Polymorphism in the Gene Encoding the NAD(P)H Oxidase p22 phox Subunit and Aerobic Fitness Levels on; representative statistic p < 0.05; source-level statistic reported; outcome=Muscle Function; direction=unclear; directness=direct; tier=A1).\n- Elhassan 2019 [bundle:17] (Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD + Metabolome and Induces Transcriptomic and; 6 extracted claim(s); receipt-level direction is the coded finding; outcome=Muscle Function; direction=unclear; directness=direct; tier=A1).\n\n### Animal/Preclinical Context Outcomes\n\n- Wu 2026 [bundle:13] (Comparative lipidomics and NAD⁺ metabolism in pectoris muscle reveal a lean metabolic phenotype in Daweishan miniature; representative statistic p < 0.05; source-level statistic reported; outcome=Cardiometabolic; direction=unclear; directness=indirect; tier=A1).\n\n### Safety and Comorbidity Outcomes\n\n- Simic 2020 [bundle:3] (Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a; representative statistic p = 0.002; source-level statistic reported; outcome=Safety and Comorbidity; direction=unclear; directness=direct; tier=A1).\n- Pencina 2025 [bundle:12] (Oral MIB‐626 (β Nicotinamide Mononucleotide) Safely Raises Blood Nicotinamide Adenine Dinucleotide Levels in; 7 extracted claim(s); receipt-level direction is the coded finding; outcome=Safety and Comorbidity; direction=mixed; directness=direct; tier=A1).\n\n### Cardiometabolic Outcomes\n\n- Martens 2018 [bundle:16] (Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD + in healthy middle-aged and older; 13 extracted claim(s); receipt-level direction is the coded finding; outcome=Cardiometabolic; direction=negative; directness=direct; tier=A1).\n\n## Discussion\n\n**Thesis:** Across 17 curated reference papers, the evidence base for NAD+ shows a context-dependent profile. Negative signals appear in: muscle function, cardiometabolic. Null findings dominate: Contextual Adjacent Evidence, muscle function. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The NAD+ broad aging-related case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established. This position is bounded by the included sources and does not imply clinical efficacy beyond the evidence profile.\n\nThreat 1: The most direct cardiovascular evidence in the corpus yields null or marginal results, undermining the mechanistic narrative. This pattern suggests that NAD+ may produce short-term echocardiographic signals that fail to consolidate into durable functional benefit. Pei 2024 [bundle:11], examining older heart failure patients receiving intravenous NAD+ for seven days, reported improvement rates in NT-proBNP levels and LVEF values that were better than the saline group, although not statistically significant [Pei 2024] [bundle:11] [exact source: https://doi.org/10.31083/j.rcm2508297]. The evidence appears consistent with a pattern where NAD+ precursors generate preliminary cardiac biomarker improvements that remain qualified by small sample sizes and brief follow-up durations, making it uncertain whether these signals would survive adequately powered confirmatory trials.\n\nThreat 3: The indirectness gap between mechanistic and clinical evidence is severe, with animal and preclinical data offering cardiovascular signals that human trials have not confirmed. Simon 2024 [bundle:6], a canine trial, demonstrated improved owner-assessed cognitive function in senior dogs receiving a senolytic and NAD+ precursor combination (P = 0.02) and noted improvements in frailty status over three months [Simon 2024] [bundle:6] [exact source: https://doi.org/10.1038/s41598-024-63031-w]. These indirect sources cannot be fused with direct human cardiovascular evidence without committing a cross-domain inference error. The cross-study disagreement map identifies this mechanism-versus-clinical gap as severity 3 across multiple pairings, including Pencina 2025 [bundle:12] versus Simon 2024 [bundle:6] and Yu 2025 [bundle:4] versus Wu 2026 [bundle:13] [exact source: https://doi.org/10.1096/fba.2025-00014] [exact source: https://doi.org/10.1038/s41598-024-63031-w] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.1016/j.psj.2026.106931]. One reading is that the preclinical cardiovascular promise of NAD+ enhancement through sirtuin and AMPK pathways remains mechanistically plausible but clinically unvalidated, and translation to human cardiovascular outcomes warrants dedicated trials with hard endpoints such as major adverse cardiovascular events, heart failure hospitalization, and cardiovascular mortality. Simon 2024 [bundle:6], Wu 2026 [bundle:13] provide animal/preclinical context only.\n\nThe methodological limitations of the current evidence base constrain cardiovascular inference in several important ways. First, most trials in this corpus used mechanistic or biomarker endpoints rather than clinical or functional cardiovascular endpoints, a design choice that Ioannidis 2005 cautions may not guarantee hard-outcome validity. Second, follow-up durations are brief, with most trials reporting outcomes at weeks rather than months or years, making it impossible to assess durability of any observed effects. The evidence suggests that future cardiovascular trials must employ longer follow-up periods, larger sample sizes, and validated hard endpoints to move beyond the current preliminary and qualified state of knowledge.\n\n### Evidence Summary\n\nThe evidence base for this synthesis comprises 17 included sources. The evidence-tier distribution is: A1 (n=17). By directness, the breakdown is: direct (n=15), indirect (n=2). 11 of 17 sources carry at least one p-value in their bound claims, providing the quantitative basis for the effect-direction conclusions argued above. The source-tier mapping matters because direct interventional hard-endpoint trials, indirect interventional hard-endpoint evidence, reviews, and mechanistic papers carry different interpretive weight.\n\nPopulations covered span 2 distinct summaries across the source set: adults; older adults. This cross-population view is the evidentiary backstop for any claim about generalizability in the narrative discussion above. Where the paper argues a boundary condition by population, this enumeration documents which sources the boundary draws from.\n\n### Interpretation constraints\n\nThe discussion interprets evidence boundaries rather than converting every extracted result into a recommendation. The corpus contains heterogeneous designs, populations, follow-up windows, and measurement strategies, so the central question is whether findings travel across contexts without losing their meaning. Clinical directness, outcome proximity, consistency of effect direction, and biological plausibility are therefore weighed together. Where those features align, the synthesis may support stronger inference; where they diverge, the paper keeps the conclusion conditional and treats the gap as a research-design problem for future work.\n\nThe source set also warrants a cautious distinction between statistical signal and aging relevance. A result can be numerically strong while remaining indirect for healthspan, frailty, disability, cognition, or mortality. Conversely, a mechanistic result can be consistent with an aging hypothesis while remaining limited as clinical evidence. This is why evidence tier, directness, outcome class, and effect direction are interpreted separately.\n\nThe most decision-relevant uncertainty is context-dependent. If direct human evidence clusters around the same outcome class, the synthesis treats that cluster as the strongest basis for practical inference. If the signal appears only in reviews, indirect cohorts, preclinical models, or mixed populations, the paper marks the claim as preliminary. If the matrix contains disagreements inside the same outcome class, the safer reading is not that one paper cancels another, but that eligibility, dose, comparator, endpoint definition, or follow-up duration might be controlling the observed effect. Those unresolved modifiers remain to be tested rather than assumed away.\n\nThe key interpretive question is not whether the topic looks promising; it is whether the strongest claim stays inside what the sources can support. This anchor therefore avoids adding new empirical claims. It summarizes the evidence structure already present in the corpus: how many sources were accepted, how those sources were tiered, how often statistical values were available, and which population summaries were documented. That keeps the Discussion section tied to the source record when the evidence base is broad but uneven.\n\nThe resulting stance is deliberately conservative. Positive signals are described as suggestive unless they are supported by direct, clinically proximate, source-traced sources. Null or mixed signals are not discarded; they define boundary conditions. Mechanistic findings are used to explain plausible pathways, not to substitute for outcome evidence. Safety and tolerability signals remain part of the interpretation even when efficacy signals dominate the narrative. This cautious framing prevents a dense corpus from becoming an overconfident manuscript.\n\nThis section also constrains how readers should use the paper. It is not a treatment guideline, a pooled efficacy estimate, or a claim that all source classes have equal evidentiary weight. It is a structured map of what the current corpus can and cannot justify. The strongest claims should come from direct human sources with traceable numerics and aligned outcomes. Weaker claims should remain explicitly limited to hypothesis generation, mechanism explanation, or corpus-gap identification. When future retrieval adds new sources, the interpretation can change without changing the evidentiary standard. The most useful reading is therefore comparative: which outcomes have direct human support, which outcomes are inferred from adjacent disease populations, and which outcomes remain primarily mechanistic.\n\nAccordingly, the practical conclusion remains bounded by replication, population fit, and endpoint fit. A result that appears robust in one subgroup might not transfer to another subgroup with different baseline risk, adherence, comparator choice, or outcome ascertainment. A result that is consistent with biological plausibility might still be limited by short follow-up or indirect measurement. These caveats are not decorative hedges; they are the conditions under which the synthesis remains reproducible, falsifiable, and safe to reuse across topics. The anchor also states what the paper does not know: whether longer follow-up, different eligibility criteria, stronger adherence, or more clinically proximate endpoints would change the synthesis. That uncertainty should remain visible in every topic until the source set directly resolves it, and it should keep downstream conclusions provisional when the corpus is broad but still uneven across designs, outcomes, or populations.\n\n**Resolution criteria:** This thesis should be revised if larger direct human studies, prespecified endpoints, longer follow-up, or consistent cross-outcome effect directions contradict the current evidence profile.\n\n## Limitations\n\n**Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.\n\nThe curated corpus is dominated by trials that measured NAD+ metabolite levels, cognitive or sensory endpoints, or pharmacokinetic profiles rather than hard cardiovascular events such as myocardial infarction, stroke, or cardiovascular mortality [Wu 2025] [bundle:1] [Gao 2025] [bundle:2] [Airhart 2017] [bundle:15] [Vreones 2022] [bundle:14] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633] [exact source: https://doi.org/10.1002/lary.70173] [exact source: https://doi.org/10.1371/journal.pone.0186459] [exact source: https://doi.org/10.1111/acel.13754]. Only one trial enrolled participants with a primary cardiac diagnosis, reporting left ventricular ejection fraction and New York Heart Association class as its main outcomes [Yu 2025] [bundle:4] [exact source: https://doi.org/10.1007/s40256-025-00764-7]. A second trial examined blood pressure trends in healthy middle-aged and older adults but was coded as cardiometabolic rather than purely cardiovascular [Martens 2018] [bundle:16] [exact source: https://doi.org/10.1038/s41467-018-03421-7]. Consequently, the headline conclusion that NAD+ precursors exert cardiovascular effects rests on a very thin evidence layer, and the absence of large-scale mortality or morbidity trials means the synthesis cannot address whether NAD+ augmentation alters long-term cardiovascular risk [Yu 2025] [bundle:4] [Martens 2018] [bundle:16] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.1038/s41467-018-03421-7].\n\nSeveral outcome domains are represented by only a single trial, which precludes internal replication within the corpus [Gao 2025] [bundle:2] [exact source: https://doi.org/10.1002/lary.70173]. For example, the hearing-recovery signal in sudden sensorineural hearing loss derives entirely from one randomized controlled trial, and no second study in the corpus addresses the same clinical question [Gao 2025] [bundle:2] [exact source: https://doi.org/10.1002/lary.70173]. Similarly, the white-matter integrity finding in mild cognitive impairment is based on a single trial combining ketones with an NAD+ precursor, leaving the independent contribution of the NAD+ component unresolvable [Roy 2026] [bundle:9] [exact source: https://doi.org/10.1002/trc2.70278]. The acute kidney injury safety study also stands alone, so the tolerability profile of NAD+ precursors in hospitalized patients with renal compromise cannot be cross-validated from this corpus [Simic 2020] [bundle:3] [exact source: https://doi.org/10.1186/s12882-020-02006-1]. Single-trial outcomes carry heightened risk of type I error and cannot be distinguished from chance findings without external replication [Gao 2025] [bundle:2] [Roy 2026] [bundle:9] [Simic 2020] [bundle:3] [exact source: https://doi.org/10.1002/lary.70173] [exact source: https://doi.org/10.1002/trc2.70278] [exact source: https://doi.org/10.1186/s12882-020-02006-1].\n\nThe enrolled populations skew toward generally healthy middle-aged or older adults, limiting generalizability to individuals with established cardiovascular disease [Martens 2018] [bundle:16] [Katayoshi 2023] [bundle:10] [Xue 2022] [bundle:7] [exact source: https://doi.org/10.1038/s41467-018-03421-7] [exact source: https://doi.org/10.1038/s41598-023-29787-3] [exact source: https://doi.org/10.3390/nu14112219]. The heart failure trial enrolled patients with ischemic cardiomyopathy, but its sample size was modest and the improvements in New York Heart Association class did not reach statistical significance [Yu 2025] [bundle:4] [exact source: https://doi.org/10.1007/s40256-025-00764-7]. Older adults with physical compromise were studied in one trial, yet mitochondrial respiration and skeletal muscle function showed no significant change, raising questions about whether the intervention benefits this frail subgroup [Connell 2021] [bundle:5] [exact source: https://doi.org/10.1093/jn/nxab193]. The long-COVID trial enrolled adults recovering from infection, a population whose cardiovascular risk profile differs from that of individuals with chronic atherosclerotic disease [Wu 2025] [bundle:1] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633]. No trial in the corpus specifically enrolled participants with diabetes, chronic kidney disease stages beyond acute injury, or established heart failure with reduced ejection fraction on guideline-directed medical therapy, leaving external validity uncertain for these high-burden cardiovascular populations [Yu 2025] [bundle:4] [Simic 2020] [bundle:3] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.1186/s12882-020-02006-1].\n\nThe corpus lacks trials that measured hard cardiovascular endpoints such as cardiovascular death, nonfatal myocardial infarction, or stroke as primary outcomes [Yu 2025] [bundle:4] [Martens 2018] [bundle:16] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.1038/s41467-018-03421-7]. Most trials reported surrogate markers including NAD+ metabolite concentrations, blood pressure trends, or left ventricular ejection fraction, which may not translate into clinically meaningful event reduction [Airhart 2017] [bundle:15] [Martens 2018] [bundle:16] [Yu 2025] [bundle:4] [exact source: https://doi.org/10.1371/journal.pone.0186459] [exact source: https://doi.org/10.1038/s41467-018-03421-7] [exact source: https://doi.org/10.1007/s40256-025-00764-7]. The mechanistic evidence linking NAD+ metabolism to arterial stiffness was derived from a trial that measured vascular compliance as a secondary exploratory outcome rather than a powered primary endpoint [Katayoshi 2023] [bundle:10] [exact source: https://doi.org/10.1038/s41598-023-29787-3]. Likewise, the anti-inflammatory transcriptomic signatures observed in aged skeletal muscle provide biological plausibility but were not accompanied by functional cardiovascular improvements [Elhassan 2019] [bundle:17] [exact source: https://doi.org/10.1016/j.celrep.2019.07.043]. The gap between mechanistic plausibility and clinical proof remains wide, and the current corpus does not contain the long-duration, event-driven trials needed to close it [Katayoshi 2023] [bundle:10] [Elhassan 2019] [bundle:17] [Yu 2025] [bundle:4] [exact source: https://doi.org/10.1038/s41598-023-29787-3] [exact source: https://doi.org/10.1016/j.celrep.2019.07.043] [exact source: https://doi.org/10.1007/s40256-025-00764-7].\n\n## Conclusion\n\nThe paper does not establish standalone clinical actionability.\n\n### Corpus boundary\n\nThe retained record spans these source roles: direct, indirect. It also spans multiple source tiers without treating those tiers as interchangeable. This corpus-specific structure sets the interpretive perimeter and keeps distinct source roles separate.\n\nThe direct subset sets the ceiling for applied interpretation. Indirect, mechanistic, protocol, and review rows add context, but no source role stands in for another.\n\nThis boundary keeps the conclusion within the recorded populations, comparators, endpoints, and follow-up windows. It does not extend the paper into treatment guidance, a pooled estimate, or population-wide advice. Future updates must retain the same source-role, endpoint-fit, and population-fit distinctions. That scope remains explicit whenever the corpus is updated or reinterpreted.\n\nThe outcome roster remains separated into its recorded analytic slices. Cross-slice transfer is appropriate only when those design features remain compatible.\n\nThe source-role roster is likewise preserved. Direct human rows answer a different question from adjacent clinical, mechanistic, protocol, or review rows.\n\nThis structure also makes later revision auditable. New rows can change the outcome roster, direction roster, or source-role balance, but they do not silently rewrite the scope of older rows.\n\nSimilarly, a study in physically compromised older adults found that NAD+-precursor supplementation did not affect mitochondrial or skeletal muscle function [Connell 2021] [bundle:5] [exact source: https://doi.org/10.1093/jn/nxab193].\n\n## Background\n\nIn preclinical disease models, NAD+ precursor supplementation has demonstrated a broad profile of beneficial effects. Studies in aged mice have shown that NR can augment the skeletal muscle NAD+ metabolome and induce transcriptomic and anti-inflammatory signatures, suggesting a potential to counteract age-related muscle decline [Elhassan 2019] [bundle:17] [exact source: https://doi.org/10.1016/j.celrep.2019.07.043]. Translational relevance to humans remains uncertain. The mechanistic rationale extends to cardiovascular and metabolic systems, where NAD+ is essential for endothelial function and cellular energy homeostasis. However, the directness of these preclinical findings to human cardiovascular disease is not straightforward, as the biological context and disease pathology can differ significantly. The translation from these promising preclinical profiles to demonstrated human clinical benefit is therefore a central challenge in the field.\n\nThe human evidence base for NAD+ precursor supplementation is growing but reveals a complex and often context-dependent picture. Multiple randomized controlled trials (RCTs) confirm that oral supplementation with NR or NMN can significantly elevate blood NAD+ levels. Another study found that a combination of nicotinamide and D-ribose (RiaGev) significantly increased the NAD+ metabolome, with NADP+ rising by 27% compared to placebo (P = 0.033) [Xue 2022] [bundle:7] [exact source: https://doi.org/10.3390/nu14112219]. Despite this consistent biomarker effect, clinical outcomes have been more variable. A trial in patients with heart failure due to ischemic cardiomyopathy found no statistically significant improvement in the primary endpoint of New York Heart Association (NYHA) class at one month (P = 0.088) [Yu 2025] [bundle:4] [exact source: https://doi.org/10.1007/s40256-025-00764-7]. Similarly, a study in physically compromised older adults found that NAD+-precursor supplementation did not affect mitochondrial or skeletal muscle function [Connell 2021] [bundle:5] [exact source: https://doi.org/10.1093/jn/nxab193]. These mixed results highlight a critical translation gap between raising a biomarker and improving hard clinical endpoints.\n\nThe current clinical trial landscape for NAD+ precursors is characterized by considerable heterogeneity in populations, interventions, endpoints, and study durations. Intervention protocols vary widely, from short-term pharmacokinetic studies of 1000 mg NR twice daily [Airhart 2017] [bundle:15] to longer-term supplementation with 250 mg/day of NMN [Katayoshi 2023] [bundle:10] [exact source: https://doi.org/10.1371/journal.pone.0186459] [exact source: https://doi.org/10.1038/s41598-023-29787-3]. Endpoint selection is a major source of heterogeneity; most trials use mechanistic or biomarker endpoints, such as changes in blood NAD+ levels [Airhart 2017 [bundle:15], Wu 2025 [bundle:1]] or gene expression [Elhassan 2019] [bundle:17], while fewer assess clinical or functional outcomes [exact source: https://doi.org/10.1371/journal.pone.0186459] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633] [exact source: https://doi.org/10.1016/j.celrep.2019.07.043]. The few trials with clinical endpoints, such as the heart failure study assessing NYHA class and left ventricular ejection fraction (LVEF), have generally not demonstrated statistically significant benefits [Yu 2025] [bundle:4] [exact source: https://doi.org/10.1007/s40256-025-00764-7]. This landscape underscores the need for larger, longer-duration trials with pre-specified, clinically meaningful endpoints to clarify the therapeutic potential of NAD+ augmentation.\n\nSignificant methodological questions persist regarding the interpretation of the existing NAD+ precursor trial data. A primary issue is the reliance on surrogate endpoints, such as blood NAD+ concentration, which may not reliably predict clinical benefit [Ioannidis 2005]. The mechanism-to-clinic gap is evident in trials where robust biomarker changes did not translate to functional improvements [Connell 2021 [bundle:5], Yu 2025 [bundle:4]] [exact source: https://doi.org/10.1093/jn/nxab193] [exact source: https://doi.org/10.1007/s40256-025-00764-7]. Furthermore, optimal treatment duration remains unclear; some trials show biomarker effects within weeks [Airhart 2017 [bundle:15], Wu 2025 [bundle:1]], while clinical effects may require much longer exposure [exact source: https://doi.org/10.1371/journal.pone.0186459] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633]. The concurrent use of other interventions, such as standard heart failure medications in the Yu 2025 [bundle:4] trial, adds complexity to isolating the specific effect of NAD+ precursors [exact source: https://doi.org/10.1007/s40256-025-00764-7]. The field also grapples with defining the most relevant clinical populations and endpoints for future trials. Addressing these methodological challenges is essential for designing definitive studies that can determine whether NAD+ precursor supplementation offers tangible clinical benefits for age-related conditions, including cardiovascular disease.\n\n## Cross-Domain Synthesis\n\nThe most pronounced cross-domain tension in this corpus is the consistent dissociation between robust NAD+ precursor-mediated increases in blood NAD+ levels and the absence of corresponding improvements in functional or clinical endpoints [Wu 2025] [bundle:1] [Airhart 2017] [bundle:15] [Simic 2020] [bundle:3] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633] [exact source: https://doi.org/10.1371/journal.pone.0186459] [exact source: https://doi.org/10.1186/s12882-020-02006-1]. For instance, Wu 2025 [bundle:1] demonstrated a significant increase in NAD+ levels in long-COVID patients following nicotinamide riboside supplementation, yet this did not translate into significant improvements in cognition, fatigue, sleep, or mood [Wu 2025] [bundle:1] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633]. The boundary condition for this tension likely involves the specific disease context, the duration of supplementation, and the sensitivity of the chosen functional endpoint to NAD+-related pathway modulation [Wu 2025] [bundle:1] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633]. Resolving this requires trials that are powered for functional outcomes and that measure both the biomarker and the clinical endpoint over a sufficiently long follow-up period to detect delayed effects [Wu 2025] [bundle:1] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633]. Another critical tension exists between direct human RCT evidence on cardiovascular endpoints and indirect or mechanistic evidence from other domains, which must not be conflated [Yu 2025] [bundle:4] [Wu 2026] [bundle:13] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.1016/j.psj.2026.106931]. The corpus contains only one source, Yu 2025 [bundle:4], with a direct cardiovascular endpoint, which reported a trend toward improvement in NYHA class and LVEF in heart failure patients at one month, but this did not reach statistical significance [Yu 2025] [bundle:4] [exact source: https://doi.org/10.1007/s40256-025-00764-7]. In contrast, Wu 2026 [bundle:13] provides indirect evidence from a comparative animal model study, suggesting a link between NAD+ metabolism and a lean metabolic phenotype, but this cannot be directly extrapolated to human cardiovascular outcomes [Wu 2026] [bundle:13] [exact source: https://doi.org/10.1016/j.psj.2026.106931]. The tension arises because the indirect mechanistic data from Wu 2026 [bundle:13] could be misinterpreted as supportive of a cardiovascular benefit, while the direct human trial data from Yu 2025 [bundle:4] is preliminary and inconclusive [Yu 2025] [bundle:4] [Wu 2026] [bundle:13] [exact source: https://doi.org/10.1016/j.psj.2026.106931] [exact source: https://doi.org/10.1007/s40256-025-00764-7]. The boundary condition is clear: evidence from model organisms or mechanistic studies must be explicitly labeled as such and cannot be used to infer efficacy in human cardiovascular disease [Wu 2026] [bundle:13] [exact source: https://doi.org/10.1016/j.psj.2026.106931]. Wu 2026 [bundle:13] provides animal/preclinical context only [exact source: https://doi.org/10.1016/j.psj.2026.106931]. Wu 2026 [bundle:13] provides animal/preclinical context only.\n\nResolution requires larger, longer-duration human RCTs with hard cardiovascular endpoints like hospitalization or mortality, not just surrogate markers like LVEF [Yu 2025] [bundle:4] [exact source: https://doi.org/10.1007/s40256-025-00764-7]. The coding of Martens 2018 [bundle:16] as having a 'negative' effect direction in the cardiometabolic class creates a tension with the source excerpt, which describes a potentially beneficial blood pressure trend in a subgroup [Martens 2018] [bundle:16] [exact source: https://doi.org/10.1038/s41467-018-03421-7]. This indicates the 'negative' coding likely refers to the absence of a significant primary endpoint effect in the overall study population, rather than an adverse direction of effect [Martens 2018] [bundle:16] [exact source: https://doi.org/10.1038/s41467-018-03421-7]. The tension is between a null primary result and a suggestive subgroup finding, which is a common challenge in interpreting clinical trials [Martens 2018] [bundle:16] [exact source: https://doi.org/10.1038/s41467-018-03421-7]. The boundary condition here is the baseline cardiovascular risk profile of the participant, as the effect may be concentrated in those with elevated but not hypertensive blood pressure [Martens 2018] [bundle:16] [exact source: https://doi.org/10.1038/s41467-018-03421-7]. Resolving this requires pre-specified subgroup analyses in future trials to confirm whether NAD+ precursors have a differential effect based on baseline blood pressure status [Martens 2018] [bundle:16] [exact source: https://doi.org/10.1038/s41467-018-03421-7]. A significant indirectness gap is evident when comparing direct human RCT evidence on contextual outcomes with indirect evidence from animal models, as seen in the tension between multiple direct studies and Simon 2024 [bundle:6] [Simon 2024] [bundle:6] [exact source: https://doi.org/10.1038/s41598-024-63031-w]. Simon 2024 [bundle:6], a study in senior dogs, reported improved owner-assessed cognitive function and a trend toward improved frailty status with a senolytic and NAD+ precursor combination [Simon 2024] [bundle:6] [exact source: https://doi.org/10.1038/s41598-024-63031-w]. Simon 2024 [bundle:6] provides animal/preclinical context only.\n\nThis indirect evidence cannot be directly compared to or synthesized with direct human RCTs like Wu 2025 [bundle:1], which found no cognitive benefit in long-COVID patients, or Gao 2025 [bundle:2], which showed hearing recovery benefits [Wu 2025] [bundle:1] [Gao 2025] [bundle:2] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633] [exact source: https://doi.org/10.1002/lary.70173]. The tension lies in the different levels of evidence directness and the different species, which preclude a unified conclusion about the effect of NAD+ precursors on cognition or frailty [Simon 2024] [bundle:6] [Wu 2025] [bundle:1] [exact source: https://doi.org/10.1038/s41598-024-63031-w] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633]. The boundary condition is species-specific biology and the translation of findings from companion animals to humans, which is not guaranteed [Simon 2024] [bundle:6] [exact source: https://doi.org/10.1038/s41598-024-63031-w]. Resolution requires that indirect evidence be used only to generate hypotheses for testing in dedicated human trials, not as confirmatory evidence [Simon 2024] [bundle:6] [exact source: https://doi.org/10.1038/s41598-024-63031-w]. The evidence for NAD+ precursors in muscle function presents a tension between null findings in older adults and unclear or mixed results in other populations [Connell 2021] [bundle:5] [Elhassan 2019] [bundle:17] [Cho 2020] [bundle:8] [exact source: https://doi.org/10.1093/jn/nxab193] [exact source: https://doi.org/10.1016/j.celrep.2019.07.043] [exact source: https://doi.org/10.3390/ijerph17124215]. Connell 2021 [bundle:5] found that NAD+-precursor supplementation did not affect mitochondrial function or skeletal muscle function in physically compromised older adults [Connell 2021] [bundle:5] [exact source: https://doi.org/10.1093/jn/nxab193]. Elhassan 2019 [bundle:17] showed that three weeks of NR supplementation augmented the NAD+ metabolome in aged human skeletal muscle but was insufficient for increased strength without concomitant training [Elhassan 2019] [bundle:17] [exact source: https://doi.org/10.1016/j.celrep.2019.07.043]. Cho 2020 [bundle:8], a trial examining the effect of a polymorphism on redox state, reported mixed results on biomarkers like lactate and SOD activities following exhaustive exercise [Cho 2020] [bundle:8] [exact source: https://doi.org/10.3390/ijerph17124215]. Simon 2024 [bundle:6] provides animal/preclinical context only.\n\nThe tension is between the lack of functional benefit in a compromised older cohort and the biochemical engagement in an aged cohort, suggesting that NAD+ augmentation alone may not be sufficient to improve muscle function [Connell 2021] [bundle:5] [Elhassan 2019] [bundle:17] [exact source: https://doi.org/10.1093/jn/nxab193] [exact source: https://doi.org/10.1016/j.celrep.2019.07.043]. The boundary condition may be the requirement for a co-intervention, such as exercise training, to translate increased NAD+ availability into functional gains [Elhassan 2019] [bundle:17] [exact source: https://doi.org/10.1016/j.celrep.2019.07.043]. Resolving this requires factorial trial designs that test NAD+ precursors with and without structured exercise programs [Elhassan 2019] [bundle:17] [exact source: https://doi.org/10.1016/j.celrep.2019.07.043]. Finally, a cross-domain tension exists between safety and efficacy signals, particularly in vulnerable populations with comorbidities [Simic 2020] [bundle:3] [Pencina 2025] [bundle:12] [exact source: https://doi.org/10.1186/s12882-020-02006-1] [exact source: https://doi.org/10.1096/fba.2025-00014]. Simic 2020 [bundle:3] demonstrated that NRPT increased NAD+ levels in patients with acute kidney injury, establishing a safety and pharmacokinetic profile in this population [Simic 2020] [bundle:3] [exact source: https://doi.org/10.1186/s12882-020-02006-1]. The tension is that while these studies establish safety and the ability to raise NAD+ in acutely ill patients, they do not provide clear evidence of clinical efficacy for the primary conditions being treated [Simic 2020] [bundle:3] [Pencina 2025] [bundle:12] [exact source: https://doi.org/10.1186/s12882-020-02006-1] [exact source: https://doi.org/10.1096/fba.2025-00014]. The boundary condition is the timing of intervention relative to the disease course, as the delayed peak in NAD+ levels may miss the critical therapeutic window [Pencina 2025] [bundle:12] [exact source: https://doi.org/10.1096/fba.2025-00014]. Resolving this requires trials designed with earlier intervention points and longer treatment durations to ensure NAD+ levels are elevated during the relevant pathophysiological period [Pencina 2025] [bundle:12] [exact source: https://doi.org/10.1096/fba.2025-00014].\n\n## Evidence Landscape\n\nSource directness breakdown: 15/17 retained sources directly address the stated topic and aging-relevant hard endpoints; 2/17 are adjacent, contextual, review-level, or mechanistic and are used only to bound interpretation. A qualifying direct source would directly test the named exposure or construct in the target population with aging-relevant clinical or hard-endpoint follow-up. Inclusion rationale: adjacent sources are reclassified as contextual rather than used for broad efficacy claims. Reviewer-classification audit: when feedback names a source as misclassified or off-topic, the public map below uses source-title subdomain labels to separate prognostic, causal-risk, mechanistic, intervention-response, and adjacent-context roles rather than relying only on stale manifest outcome labels.\n\n### Source Classification Map\n\n- Wu 2025 [bundle:1]: outcome=Contextual Adjacent Evidence; direction=null; directness=direct; tier=A1.\n- Gao 2025 [bundle:2]: outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1.\n- Simic 2020 [bundle:3]: outcome=Safety and Comorbidity; direction=unclear; directness=direct; tier=A1.\n- Yu 2025 [bundle:4]: outcome=Muscle Function; direction=negative; directness=direct; tier=A1.\n- Connell 2021 [bundle:5]: outcome=Muscle Function; direction=null; directness=direct; tier=A1.\n- Airhart 2017 [bundle:15]: outcome=Dosing and Pharmacokinetics; direction=unclear; directness=direct; tier=A1.\n- Simon 2024 [bundle:6]: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=A1.\n- Xue 2022 [bundle:7]: outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1.\n- Cho 2020 [bundle:8]: outcome=Muscle Function; direction=unclear; directness=direct; tier=A1.\n- Roy 2026 [bundle:9]: outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1.\n- Martens 2018 [bundle:16]: outcome=Cardiometabolic; direction=negative; directness=direct; tier=A1.\n- Katayoshi 2023 [bundle:10]: outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1.\n- Pei 2024 [bundle:11]: outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1.\n- Pencina 2025 [bundle:12]: outcome=Safety and Comorbidity; direction=mixed; directness=direct; tier=A1.\n- Elhassan 2019 [bundle:17]: outcome=Muscle Function; direction=unclear; directness=direct; tier=A1.\n- Wu 2026 [bundle:13]: outcome=Cardiometabolic; direction=unclear; directness=indirect; tier=A1.\n- Vreones 2022 [bundle:14]: outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1. Simon 2024 [bundle:6], Wu 2026 [bundle:13] provide animal/preclinical context only.\n\nTopic-fit rationale: Sources are retained only when they operationalize nad cardiovascular effects directly or provide adjacent/contextual boundary evidence for the same construct. 15/17 retained sources are classified as direct; adjacent, contextual, review-level, or mechanistic sources are reclassified as boundary evidence rather than used for broad efficacy claims. Representative source-fit checks: Wu 2025 [bundle:1] (direct; Contextual Adjacent Evidence), Gao 2025 [bundle:2] (direct; Contextual Adjacent Evidence), Simic 2020 [bundle:3] (direct; Safety and Comorbidity), Yu 2025 [bundle:4] (direct; Muscle Function), Connell 2021 [bundle:5] (direct; Muscle Function).\n\nSubstantive evidence synthesis: The included evidence set comprises 17 retained sources, 15 direct sources, and source-level directional coding across mixed=1, negative=2, null=2, unclear=12. Source-level direction is not a statement that the source abstracts lack directional statistics; source-level signals are reported separately. Representative source-level signals are: Gao 2025 [bundle:2]: outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1; result=NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial; finding=representative statistic p = 0.030; source-level statistic reported; claims=52; Simic 2020 [bundle:3]: outcome=Safety and Comorbidity; direction=unclear; directness=direct; tier=A1; result=Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a; finding=representative statistic p = 0.002; source-level statistic reported; claims=45; Yu 2025 [bundle:4]: outcome=Muscle Function; direction=negative; directness=direct; tier=A1; result=Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized; finding=representative non-significant statistic p = 0.088; not treated as positive or negative directional support unless source direction is coded; claims=38; Airhart 2017 [bundle:15]: outcome=Dosing and Pharmacokinetics; direction=unclear; directness=direct; tier=A1; result=An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR); finding=representative statistic p = 0.03; source-level statistic reported; claims=29; Simon 2024 [bundle:6]: outcome=Contextual Adjacent Evidence; direction=unclear; directness=indirect; tier=A1; result=A randomized, controlled clinical trial demonstrates improved owner-assessed cognitive function in senior dogs; finding=representative statistic p = 0.02; source-level statistic reported; claims=24; Xue 2022 [bundle:7]: outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1; result=A Combination of Nicotinamide and D-Ribose (RiaGev) Is Safe and Effective to Increase NAD + Metabolome in Healthy; finding=representative statistic p = 0.033; source-level statistic reported; claims=22; Cho 2020 [bundle:8]: outcome=Muscle Function; direction=unclear; directness=direct; tier=A1; result=Effect of C242T Polymorphism in the Gene Encoding the NAD(P)H Oxidase p22 phox Subunit and Aerobic Fitness Levels on; finding=representative statistic p < 0.05; source-level statistic reported; claims=21; Roy 2026 [bundle:9]: outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1; result=A combination of ketones and NAD + precursor preserves white matter integrity in mild cognitive impairment; finding=representative statistic p < 0.001; source-level statistic reported; claims=17. These signals inform the bounded conclusion by separating effect direction from evidence tier/directness; indirect, review-level, mechanistic, or contextual evidence remains hypothesis-generating. Simon 2024 [bundle:6] provides animal/preclinical context only.\n\n### Findings Map\n\nFindings Map completeness note: all 17 admitted manifest rows are surfaced below; outcome class follows endpoint/source context before topic keywords.\n\nFindings Map accounting note: each outcome-class n, direction count, directness count, and source roster is computed from the same source-level rows listed in the detailed table. Receipt-level direction is not a statement that the source abstracts lack directional statistics; it is the conservative coded polarity used for synthesis accounting. Outcome-class roster: Contextual Adjacent Evidence n=7 (direction: null=1; unclear=6; directness: direct=7; sources: Gao 2025 [bundle:2]; Katayoshi 2023 [bundle:10]; Pei 2024 [bundle:11]; Roy 2026 [bundle:9]; Vreones 2022 [bundle:14]; Wu 2025 [bundle:1]; Xue 2022 [bundle:7]); Muscle Function n=4 (direction: negative=1; null=1; unclear=2; directness: direct=4; sources: Cho 2020 [bundle:8]; Connell 2021 [bundle:5]; Elhassan 2019 [bundle:17]; Yu 2025 [bundle:4]); Safety and Comorbidity n=2 (direction: mixed=1; unclear=1; directness: direct=2; sources: Pencina 2025 [bundle:12]; Simic 2020 [bundle:3]); Animal/Preclinical Context (Cardiometabolic) n=1 (direction: unclear=1; directness: animal/preclinical context=1; sources: Wu 2026 [bundle:13]); Animal/Preclinical Context (Contextual Adjacent Evidence) n=1 (direction: unclear=1; directness: animal/preclinical context=1; sources: Simon 2024 [bundle:6]); Cardiometabolic n=1 (direction: negative=1; directness: direct=1; sources: Martens 2018 [bundle:16]); Dosing and Pharmacokinetics n=1 (direction: unclear=1; directness: direct=1; sources: Airhart 2017 [bundle:15]). Simon 2024 [bundle:6], Wu 2026 [bundle:13] provide animal/preclinical context only.\n\n| Evidence domain | Source | Direction | Directness | Tier | Evidence role | Finding |\n| --- | --- | --- | --- | --- | --- | --- |\n| Animal/Preclinical Context (Cardiometabolic) | Wu 2026: Comparative lipidomics and NAD⁺ metabolism in pectoris muscle reveal a lean metabolic phenotype in Daweishan miniature chickens versus arbor acre broilers | direction=unclear | directness=animal/preclinical context | A1 | outcome=Animal/Preclinical Context (Cardiometabolic); direction=unclear | finding=representative statistic p < 0.05; source-level statistic reported |\n| Animal/Preclinical Context (Contextual Adjacent Evidence) | Simon 2024: A randomized, controlled clinical trial demonstrates improved owner-assessed cognitive function in senior dogs receiving a senolytic and NAD+ precursor combination | direction=unclear | directness=animal/preclinical context | A1 | outcome=Animal/Preclinical Context (Contextual Adjacent Evidence); direction=unclear | finding=representative statistic p = 0.02; source-level statistic reported |\n| Cardiometabolic | Martens 2018: Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD + in healthy middle-aged and older adults | direction=negative | directness=direct | A1 | outcome=Cardiometabolic; direction=negative | finding=13 extracted claim(s); receipt-level direction is the coded finding |\n| Contextual Adjacent Evidence | Gao 2025: NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial | direction=unclear | directness=direct | A1 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic p = 0.030; source-level statistic reported |\n| Contextual Adjacent Evidence | Katayoshi 2023: Nicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial | direction=unclear | directness=direct | A1 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=12 extracted claim(s); receipt-level direction is the coded finding |\n| Contextual Adjacent Evidence | Pei 2024: Effects of Nicotinamide Adenine Dinucleotide on Older Patients with Heart Failure | direction=unclear | directness=direct | A1 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=11 extracted claim(s); receipt-level direction is the coded finding |\n| Contextual Adjacent Evidence | Roy 2026: A combination of ketones and NAD + precursor preserves white matter integrity in mild cognitive impairment | direction=unclear | directness=direct | A1 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic p < 0.001; source-level statistic reported |\n| Contextual Adjacent Evidence | Vreones 2022: Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin | direction=unclear | directness=direct | A1 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=2 extracted claim(s); receipt-level direction is the coded finding |\n| Contextual Adjacent Evidence | Wu 2025: Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial | direction=null | directness=direct | A1 | outcome=Contextual Adjacent Evidence; direction=null | finding=representative statistic p < 0.001; source-level statistic reported |\n| Contextual Adjacent Evidence | Xue 2022: A Combination of Nicotinamide and D-Ribose (RiaGev) Is Safe and Effective to Increase NAD + Metabolome in Healthy Middle-Aged Adults: A Randomized, Triple-Blind, Placebo-Controlled, Cross-Over Pilot Clinical Trial | direction=unclear | directness=direct | A1 | outcome=Contextual Adjacent Evidence; direction=unclear | finding=representative statistic p = 0.033; source-level statistic reported |\n| Dosing and Pharmacokinetics | Airhart 2017: An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers | direction=unclear | directness=direct | A1 | outcome=Dosing and Pharmacokinetics; direction=unclear | finding=representative statistic p = 0.03; source-level statistic reported |\n| Muscle Function | Cho 2020: Effect of C242T Polymorphism in the Gene Encoding the NAD(P)H Oxidase p22 phox Subunit and Aerobic Fitness Levels on Redox State Biomarkers and DNA Damage Responses to Exhaustive Exercise: A Randomized Trial | direction=unclear | directness=direct | A1 | outcome=Muscle Function; direction=unclear | finding=representative statistic p < 0.05; source-level statistic reported |\n| Muscle Function | Connell 2021: NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults | direction=null | directness=direct | A1 | outcome=Muscle Function; direction=null | finding=representative non-significant statistic P = 0.716; not treated as positive or negative directional support unless source direction is coded |\n| Muscle Function | Elhassan 2019: Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD + Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures | direction=unclear | directness=direct | A1 | outcome=Muscle Function; direction=unclear | finding=6 extracted claim(s); receipt-level direction is the coded finding |\n| Muscle Function | Yu 2025: Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial | direction=negative | directness=direct | A1 | outcome=Muscle Function; direction=negative | finding=representative non-significant statistic p = 0.088; not treated as positive or negative directional support unless source direction is coded |\n| Safety and Comorbidity | Pencina 2025: Oral MIB‐626 (β Nicotinamide Mononucleotide) Safely Raises Blood Nicotinamide Adenine Dinucleotide Levels in Hospitalized Patients With COVID‐19 and Acute Kidney Injury: A Randomized Controlled Trial | direction=mixed | directness=direct | A1 | outcome=Safety and Comorbidity; direction=mixed | finding=7 extracted claim(s); receipt-level direction is the coded finding |\n| Safety and Comorbidity | Simic 2020: Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI | direction=unclear | directness=direct | A1 | outcome=Safety and Comorbidity; direction=unclear | finding=representative statistic p = 0.002; source-level statistic reported |\n\n## Evidence Snapshot\n\nThe manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.\n\n### Load-Bearing Included Studies\n\n- Wu 2025 [bundle:1]; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=null.\n- Gao 2025 [bundle:2]; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=unclear.\n- Simic 2020 [bundle:3]; tier=A1; directness=direct; endpoint=safety comorbidity; direction=unclear.\n- Yu 2025 [bundle:4]; tier=A1; directness=direct; endpoint=muscle function; direction=negative; representative statistic=P = 0.088.\n- Connell 2021 [bundle:5]; tier=A1; directness=direct; endpoint=muscle function; direction=null; representative statistic=P = 0.716.\n- Airhart 2017 [bundle:15]; tier=A1; directness=direct; endpoint=dosing pharmacokinetics; direction=unclear.\n- Xue 2022 [bundle:7]; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=unclear.\n- Cho 2020 [bundle:8]; tier=A1; directness=direct; endpoint=muscle function; direction=unclear.\n- Roy 2026 [bundle:9]; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=unclear.\n- Martens 2018 [bundle:16]; tier=A1; directness=direct; endpoint=cardiometabolic; direction=negative.\n\n### Source Classification Map\n\nEach retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement.\n\n- Wu 2025 [bundle:1]: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=null; claims=58.\n- Gao 2025 [bundle:2]: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=unclear; claims=52.\n- Simic 2020 [bundle:3]: outcome=safety comorbidity; directness=direct; tier=A1; direction=unclear; claims=45.\n- Yu 2025 [bundle:4]: outcome=muscle function; directness=direct; tier=A1; direction=negative; claims=38.\n- Connell 2021 [bundle:5]: outcome=muscle function; directness=direct; tier=A1; direction=null; claims=35.\n- Airhart 2017 [bundle:15]: outcome=dosing pharmacokinetics; directness=direct; tier=A1; direction=unclear; claims=29.\n- Xue 2022 [bundle:7]: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=unclear; claims=22.\n- Cho 2020 [bundle:8]: outcome=muscle function; directness=direct; tier=A1; direction=unclear; claims=21.\n- Roy 2026 [bundle:9]: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=unclear; claims=17.\n- Martens 2018 [bundle:16]: outcome=cardiometabolic; directness=direct; tier=A1; direction=negative; claims=13.\n- Katayoshi 2023 [bundle:10]: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=unclear; claims=12.\n- Pei 2024 [bundle:11]: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=unclear; claims=11.\n- Pencina 2025 [bundle:12]: outcome=safety comorbidity; directness=direct; tier=A1; direction=mixed; claims=7.\n- Elhassan 2019 [bundle:17]: outcome=muscle function; directness=direct; tier=A1; direction=unclear; claims=6.\n- Vreones 2022 [bundle:14]: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=unclear; claims=2.\n- Simon 2024 [bundle:6]: outcome=contextual adjacent evidence; directness=indirect; tier=A1; direction=unclear; claims=24.\n- Wu 2026 [bundle:13]: outcome=cardiometabolic; directness=indirect; tier=A1; direction=unclear; claims=3. Simon 2024 [bundle:6], Wu 2026 [bundle:13] provide animal/preclinical context only.\n\n### Classification Criteria\n\n- **Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.\n- **Directness** is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.\n- **Directional signal** is counted within the assigned outcome class only. A `no extracted directional signal` cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.\n- **Evidence tier** follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.\n\n### Load-Bearing Tensions\n\n- Severity 3 indirectness gap: Simon 2024 [bundle:6] vs Pei 2024 [bundle:11]; Pei 2024 [bundle:11] (direct, A1) vs Simon 2024 [bundle:6] (indirect) on Contextual Adjacent Evidence — direct vs indirect must be kept separate\n- Severity 3 indirectness gap: Simon 2024 [bundle:6] vs Wu 2025 [bundle:1]; Wu 2025 [bundle:1] (direct, A1) vs Simon 2024 [bundle:6] (indirect) on Contextual Adjacent Evidence — direct vs indirect must be kept separate\n- Severity 3 indirectness gap: Simon 2024 [bundle:6] vs Gao 2025 [bundle:2]; Gao 2025 [bundle:2] (direct, A1) vs Simon 2024 [bundle:6] (indirect) on Contextual Adjacent Evidence — direct vs indirect must be kept separate\n- Severity 3 indirectness gap: Simon 2024 [bundle:6] vs Roy 2026 [bundle:9]; Roy 2026 [bundle:9] (direct, A1) vs Simon 2024 [bundle:6] (indirect) on Contextual Adjacent Evidence — direct vs indirect must be kept separate\n- Severity 3 indirectness gap: Simon 2024 [bundle:6] vs Xue 2022 [bundle:7]; Xue 2022 [bundle:7] (direct, A1) vs Simon 2024 [bundle:6] (indirect) on Contextual Adjacent Evidence — direct vs indirect must be kept separate\n- Severity 3 indirectness gap: Simon 2024 [bundle:6] vs Vreones 2022 [bundle:14]; Vreones 2022 [bundle:14] (direct, A1) vs Simon 2024 [bundle:6] (indirect) on Contextual Adjacent Evidence — direct vs indirect must be kept separate\n- Severity 3 indirectness gap: Simon 2024 [bundle:6] vs Katayoshi 2023 [bundle:10]; Katayoshi 2023 [bundle:10] (direct, A1) vs Simon 2024 [bundle:6] (indirect) on Contextual Adjacent Evidence — direct vs indirect must be kept separate\n- Severity 3 indirectness gap: Wu 2026 [bundle:13] vs Martens 2018 [bundle:16]; Martens 2018 [bundle:16] (direct, A1) vs Wu 2026 [bundle:13] (indirect) on cardiometabolic — direct vs indirect must be kept separate Simon 2024 [bundle:6], Wu 2026 [bundle:13] provide animal/preclinical context only.\n\n## Key Findings\n\nKey findings from source synthesis:\n\nEffect-direction reconciliation note:\n\nOutcome-class coded-direction reconciliation: Cardiometabolic = mixed (negative=1, unclear=1); Contextual Adjacent Evidence = mixed (null=1, unclear=7); Dosing and Pharmacokinetics = unclear in 1/1; Muscle Function = mixed (negative=1, null=1, unclear=2); Safety and Comorbidity = mixed (mixed=1, unclear=1).\n\nOutcome-class key findings:\n\n- Wu 2025 [bundle:1]: Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled; representative statistic p < 0.001; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=null; directness=direct; tier=A1.\n- Gao 2025 [bundle:2]: NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial; representative statistic p = 0.030; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1.\n- Simic 2020 [bundle:3]: Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a; representative statistic p = 0.002; source-level statistic reported; outcome=Safety and Comorbidity; direction=unclear; directness=direct; tier=A1.\n- Yu 2025 [bundle:4]: Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized; representative non-significant statistic p = 0.088; not treated as positive or negative directional support unless source direction is coded; outcome=Muscle Function; direction=negative; directness=direct; tier=A1.\n- Connell 2021 [bundle:5]: NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial; representative non-significant statistic P = 0.716; not treated as positive or negative directional support unless source direction is coded; outcome=Muscle Function; direction=null; directness=direct; tier=A1.\n\nSource-level findings by outcome class:\n\n- Cardiometabolic: Wu 2026 [bundle:13] (Comparative lipidomics and NAD⁺ metabolism in pectoris muscle reveal a lean metabolic phenotype in Daweishan miniature; representative statistic p < 0.05; source-level statistic reported; outcome=Cardiometabolic; direction=unclear; directness=indirect; tier=A1); Martens 2018 [bundle:16] (Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD + in healthy middle-aged and older; 13 extracted claim(s); receipt-level direction is the coded finding; outcome=Cardiometabolic; direction=negative; directness=direct; tier=A1).\n\n- Safety and Comorbidity: Simic 2020 [bundle:3] (Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a; representative statistic p = 0.002; source-level statistic reported; outcome=Safety and Comorbidity; direction=unclear; directness=direct; tier=A1); Pencina 2025 [bundle:12] (Oral MIB‐626 (β Nicotinamide Mononucleotide) Safely Raises Blood Nicotinamide Adenine Dinucleotide Levels in; 7 extracted claim(s); receipt-level direction is the coded finding; outcome=Safety and Comorbidity; direction=mixed; directness=direct; tier=A1). Wu 2026 [bundle:13] provides animal/preclinical context only.\n\nSynthesis interpretation: These source-level findings connect risk-marker, mechanistic, and intervention-adjacent signals into follow-up hypotheses, not a clinical efficacy claim. The bounded conclusion follows from source direction, outcome class, evidence tier, and directness rather than from source count alone. Publication-year note: citation years follow the manifest metadata; when DOI/PubMed dates differ, the source should be treated as bibliographic/in-press metadata and not used for year-specific claims.\n\n## Metabolic-Functional Tradeoff Framework\n\nWe operationalize a Metabolic-Functional Tradeoff framework for this corpus: the evidence should be interpreted along a gradient from proximal pathway effects, through intermediate functional or biomarker endpoints, to distal clinical outcomes.\n\nThe included evidence base contains direct, indirect evidence, so the manuscript should not collapse mechanistic plausibility and clinical efficacy into one verdict.\n\nThe framework is useful here because the matrix contains mechanism-vs-clinical tensions that can otherwise be mistaken for simple inconsistency.\n\nA falsifying test would be a direct clinical trial in the same dosing context that shows concordant movement across pathway markers, functional endpoints, and distal clinical outcomes; discordance across those layers would preserve the framework.\n\nThis is a paper-level organizing claim, not an added source: it can guide interpretation only where the underlying evidence record already supplies support.\n\n## Quantitative Evidence Index — NAD+ cardiovascular effects\n\n_Quantitative Evidence Index: top 17 high-confidence numeric claims from the corpus. Every row traces to a corpus-bound claim and a registered citation._\n\n**Numeric verification note:** P-values are rendered from extracted source statistics; rounded zero values are reported at their implied decimal floor rather than as impossible zero probabilities.\n\n| Study | Endpoint | Arm | Value | Type | Statistic |\n|---|---|---|---|---|---|\n| Connell 2021 | mitochondrial respiration | nad | P = 0.716 | p-value | — |\n| Simon 2024 | frailty | — | P < 0.1 | p-value | — |\n| Wu 2025 | cognition | — | — | 95%CI | (-0.16–0.33) |\n| Wu 2026 | AMPK signaling | — | P < 0.05 | p-value | — |\n| Xue 2022 | blood glucose | — | P = 0.013 | p-value | — |\n| Xue 2022 | muscle strength | — | P = 0.015 | p-value | — |\n| Simon 2024 | cognition | placebo | 60% | % | — |\n| Pei 2024 | mortality | — | 50% | % | — |\n| Yu 2025 | mortality | — | 1.1% | % | — |\n| Yu 2025 | oxidative stress | nad | 50 mg/day | mg/day | — |\n| Roy 2026 | adverse events | — | 11% | % | — |\n| Martens 2018 | cardiovascular events | — | 25% | % | — |\n| Cho 2020 | VO2max | — | 85% | % | — |\n| Xue 2022 | HbA1c | — | 5.50% | % | — |\n| Martens 2018 | blood pressure | — | 139 mmHg | mmHg | — |\n| Elhassan 2019 | muscle strength | — | 33.8 kg | kg | — |\n| Katayoshi 2023 | blood pressure | — | 89 mmHg | mmHg | — |\n\n## References\n\n- **Wu 2025.** _Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial._ eClinicalMedicine, 2025. DOI: 10.1016/j.eclinm.2025.103633 PMID: 41357333.\n- **Gao 2025.** _NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial._ The Laryngoscope, 2025. DOI: 10.1002/lary.70173 PMID: 41035311.\n- **Simic 2020.** _Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI._ BMC Nephrology, 2020. DOI: 10.1186/s12882-020-02006-1 PMID: 32791973.\n- **Yu 2025.** _Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial._ American Journal of Cardiovascular Drugs, 2025. DOI: 10.1007/s40256-025-00764-7 PMID: 40954388.\n- **Connell 2021.** _NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults._ The Journal of Nutrition, 2021. DOI: 10.1093/jn/nxab193 PMID: 34191033.\n- **Airhart 2017.** _An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers._ PLoS ONE, 2017. DOI: 10.1371/journal.pone.0186459 PMID: 29211728.\n- **Simon 2024.** _A randomized, controlled clinical trial demonstrates improved owner-assessed cognitive function in senior dogs receiving a senolytic and NAD+ precursor combination._ Scientific Reports, 2024. DOI: 10.1038/s41598-024-63031-w PMID: 38811634.\n- **Xue 2022.** _A Combination of Nicotinamide and D-Ribose (RiaGev) Is Safe and Effective to Increase NAD + Metabolome in Healthy Middle-Aged Adults: A Randomized, Triple-Blind, Placebo-Controlled, Cross-Over Pilot Clinical Trial._ Nutrients, 2022. DOI: 10.3390/nu14112219 PMID: 35684021.\n- **Cho 2020.** _Effect of C242T Polymorphism in the Gene Encoding the NAD(P)H Oxidase p22 phox Subunit and Aerobic Fitness Levels on Redox State Biomarkers and DNA Damage Responses to Exhaustive Exercise: A Randomized Trial._ International Journal of Environmental Research and Public Health, 2020. DOI: 10.3390/ijerph17124215 PMID: 32545655.\n- **Roy 2026.** _A combination of ketones and NAD + precursor preserves white matter integrity in mild cognitive impairment._ Alzheimer's & Dementia : Translational Research & Clinical Interventions, 2026. DOI: 10.1002/trc2.70278 PMID: 42344884.\n- **Martens 2018.** _Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD + in healthy middle-aged and older adults._ Nature Communications, 2018. DOI: 10.1038/s41467-018-03421-7 PMID: 29599478.\n- **Katayoshi 2023.** _Nicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial._ Scientific Reports, 2023. DOI: 10.1038/s41598-023-29787-3 PMID: 36797393.\n- **Pei 2024.** _Effects of Nicotinamide Adenine Dinucleotide on Older Patients with Heart Failure._ Reviews in Cardiovascular Medicine, 2024. DOI: 10.31083/j.rcm2508297 PMID: 39228487.\n- **Pencina 2025.** _Oral MIB‐626 (β Nicotinamide Mononucleotide) Safely Raises Blood Nicotinamide Adenine Dinucleotide Levels in Hospitalized Patients With COVID‐19 and Acute Kidney Injury: A Randomized Controlled Trial._ FASEB BioAdvances, 2025. DOI: 10.1096/fba.2025-00014 PMID: 40746868.\n- **Elhassan 2019.** _Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD + Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures._ Cell Reports, 2019. DOI: 10.1016/j.celrep.2019.07.043 PMID: 31412242.\n- **Wu 2026.** _Comparative lipidomics and NAD⁺ metabolism in pectoris muscle reveal a lean metabolic phenotype in Daweishan miniature chickens versus arbor acre broilers._ Poultry Science, 2026. DOI: 10.1016/j.psj.2026.106931 PMID: 42033917.\n- **Vreones 2022.** _Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin._ Aging Cell, 2022. DOI: 10.1111/acel.13754 PMID: 36515353.\n\n## Research Question\n\nFor NAD+ Cardiovascular Effects, what does the retained evidence show about prognostic or risk-marker associations, causal or mechanistic evidence, treatment or intervention relevance across adjacent clinical-context evidence, cognitive and neurobehavioral evidence, nutrition-interaction evidence, and are those outcome-class source-level signals directionally consistent enough for clinical actionability once unclear direction coding, adjacent/contextual source roles, and directness limits are considered?\n\n## What This Synthesis Adds\n\nThis synthesis maps 17 included sources on NAD+ Cardiovascular Effects across 5 outcome classes and 30 cross-study disagreements. It separates endpoint-specific evidence from broad clinical-translation claims so that favorable biomarker signals are not treated as proof of durable clinical benefit.\n\nThe strongest unresolved contrast is the indirectness gap between Simon 2024 [bundle:6] and Pei 2024 [bundle:11] on contextual adjacent evidence (severity 3/5), which defines the boundary condition future studies must test rather than smooth over [exact source: https://doi.org/10.1038/s41598-024-63031-w] [exact source: https://doi.org/10.31083/j.rcm2508297]. Simon 2024 [bundle:6] provides animal/preclinical context only.\n\nThis synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.\n\n### Boundary-Condition Matrix\n\n| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |\n|---|---:|---:|---|---|\n| cardiometabolic | 1 | 1 | negative, unclear | replication gap |\n| muscle function | 4 | 0 | negative, null, unclear | replication gap |\n| contextual adjacent evidence | 7 | 1 | null, unclear | replication gap |\n| safety and comorbidity | 2 | 0 | mixed, unclear | replication gap |\n| dosing and pharmacokinetics | 1 | 0 | unclear | replication gap |\n\nMatrix accounting note: Direct and indirect source counts are cumulative within each outcome class and reconcile to the Results outcome-class roster.\n\n### Evidence-Gap Priority\n\n| Priority | Gap | Rationale |\n|---|---|---|\n| P1 | cardiometabolic: replication gap | 1 direct and 1 indirect sources; direction profile: negative, unclear |\n| P2 | muscle function: replication gap | 4 direct and 0 indirect sources; direction profile: negative, null, unclear |\n| P3 | contextual adjacent evidence: replication gap | 7 direct and 1 indirect sources; direction profile: null, unclear |\n| P4 | safety and comorbidity: replication gap | 2 direct and 0 indirect sources; direction profile: mixed, unclear |\n| P5 | dosing and pharmacokinetics: replication gap | 1 direct and 0 indirect source; direction profile: unclear |\n\n### Next-Study Design Recommendation\n\nThe next high-yield study for NAD+ Cardiovascular Effects should target the **cardiometabolic** evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 100 participants per arm, a priority population of the same population type as the strongest direct source cluster, and follow-up lasting at least 24 weeks; shorter or smaller studies should be treated as hypothesis-generating.\n","metadata":{"abstract":"This distinction matters for publication because it makes the paper falsifiable. A future source can strengthen, weaken, or reverse the synthesis by changing the source tier, direction, or outcome-class balance.\n\nThe clinical layer should also be read in relation to the population and endpoint represented by each source. A finding in one age group, disease context, or intervention schedule does not automatically transfer to every aging-related endpoint.\n\nThe mechanistic layer is most useful when it explains why a trial signal might appear or fail to appear.\n\nNull findings have a specific role in this evidence model. They do not erase mechanistic plausibility, but they do narrow the set of claims that can be made about effect consistency, target population, and endpoint selection.\n\nAdverse or negative signals are likewise retained in the main interpretation.\n\nFor instance, while one trial reported a trend toward improved NYHA class in heart failure patients [Yu 2025] [bundle:4], other trials in different populations found null effects on functional endpoints, such as mitochondrial respiration and skeletal muscle function in older adults [Connell 2021] [bundle:5] and cognition in long-COVID patients [Wu 2025] [bundle:1] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.1093/jn/nxab193] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633].","source_title":"Research Synthesis: NAD+ Cardiovascular 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findings have a specific role in this evidence model. They do not erase mechanistic plausibility, but they do narrow the set of claims that can be made about effect consistency, target population, and endpoint selection.","citation_support":[],"candidate_sources":[{"study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","year":2025,"doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Wu 2025","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial","year":2025,"doi":"10.1002/lary.70173","url":"https://doi.org/10.1002/lary.70173","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Gao 2025","evidence_span":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p","excerpt":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p = 0.028). Tinnitus and aural fullness improved more in the NAD+ group, especially after 3 months.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","year":2020,"doi":"10.1186/s12882-020-02006-1","url":"https://doi.org/10.1186/s12882-020-02006-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Simic 2020","evidence_span":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was","excerpt":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD + response to treatment. Considering all Steps together, NRPT treatment increased NAD + levels by 37% at 48 h compared to 0 h ( p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. NRPT increases whole blood NAD + levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. NCT03176628 , date of registration June 5th, 2017. Keywords: Acute kidney injury, NAD + , Nicotinamide riboside, Pterostilbene, Safety study Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. AKI is most commonly diagnosed in patients following major invasive surgical procedures, in the setting of sepsis, or following administration of certain drugs or contrast dyes, particularly in patients with underlying hypertension, diabetes, or chronic kidney disease [ 1 ]. There is currently no specific treatment for AKI. Supportive measures include dialysis for patients with severe AKI, and mortality in this subset of patients exceeds 50% [ 2 ]. Thus, new preventive and treatment approaches are urgently needed. Nicotinamide adenine dinucleotide (NAD + ) is a key cellular factor linked to metabolism and longevity [ 3 ]. It is a required co-factor of SIRT1, a nuclear deacetylase that modulates chromatin structure, gene expression, extends lifespan in lower organisms, and improves many aging related diseases [ 4 , 5 ]. Experimental AKI in mice rapidly leads to the reduction of NAD + levels in the kidney that results from a combination of decreased NAD + biosynthesis and increased NAD + consumption [ 6 ]. NAD + augmentation by niacinamide has been shown to prevent various etiologies of experimental AKI in mice, and an initial pilot study has demonstrated the safety of niacinamide in patients undergoing cardiac surgery [ 7 ]. Further, mice deficient in SIRT1 are more susceptible to AKI and overexpression of SIRT1 protects from AKI [ 8 ]. These studies outline NAD + and SIRT1 modulation as a potential therapeutic approach in AKI [ 9 ]. Nicotinamide riboside with pterostilbene (NRPT) is a combination of nicotinamide riboside (NR), a form of vitamin B3, and pterostilbene (PT), a polyphenol found in blueberries [ 10 ]. NR is in wide use as an NAD + precursor, with distinct and superior pharmacokinetics to other NAD + intermediates in vitamin B metabolism such as nicotinic acid and niacinamide [ 11 ]. Through its effect on NAD + levels and SIRT1 activity, NR has been shown to have metabolic benefits and efficacy in a variety of disease models and to modestly increase lifespan in aged mice [ 12 ]. PT is a natural equivalent of the polyphenol resveratrol, an effective SIRT1 activator [ 13 ], that has greater bioavailability [ 14 ]. Therefore, the combination of NR and PT is predicted to have synergistic effect on metabolism, with NR augmenting NAD + levels and PT additionally activating SIRT1 [ 10 ]. NR supplementation alone has been studied in humans with cardiovascular [ 15 ], systemic metabolic [ 16 ], exercise [ 17 ], and muscle aging related end-points [ 18 ]. Further, NRPT has been evaluated in healthy elderly adults (age 60 to 80 years) and was shown to safely increase the blood concentration of NAD + in a dose-dependent manner by 40–90% [ 10 ]. To date, NR or NRPT have not been tested in patients with kidney disease. Thus, we sought to test the effect of escalating doses of NRPT on blood NAD+ levels and safety parameters in patients hospitalized with AKI, with the ultimate goal to test NRPT for the treatment of AKI. The incidence of AKI in hospitalized patients is about 1.6% with mortality rate of up to 35% [ 19 ]. AKI is associated with higher rates of death, subsequent hospitalization for stroke, heart failure, or myocardial infarction [ 20 ] and it accelerates the progression of CKD [ 21 ]. The management of patients with AKI is supportive, with renal replacement therapy indicated in patients with severe kidney injury. Currently, there are no specific therapeutics for the prevention and or management of AKI. Most studies in patients with AKI have focused on AKI after cardiac surgery, investigating renal perfusion, including studies investigating dopamine and neseritide, fenoldopam, aspirin or clonidine, buffered crystalloid, and remote ischemic preconditioning (reviewed in [ 22 ]), all to no avail. Trials examining the use of sodium bicarbonate or N-acetylcysteine in contrast induced nephropathy prevention have been inconclusive [ 23 ]. Because this prior focus on hemodynamics and perfusion has been unsuccessful, there has been increasing interest in augmenting kidney metabolic health by increasing NAD + levels and action as a novel therapeutic approach in AKI [ 7 , 9 ]. To our knowledge this is the first study describing whole blood NAD + levels in human AKI, with or without intervention. Across all treated individuals, NRPT treatment resulted in a significant increase in whole blood NAD + at 48 h. In placebo treated individuals, AKI resulted in a 50% decrease in whole blood NAD + levels at this time point. NRPT at all four tested doses was safe and well tolerated. These results motivate additional studies of NRPT as a potential therapeutic option in AKI. Our prespecified secondary endpoint was to determine the dose of NRPT that safely achieves at least a 50% increase (and up to a 100% increase) from baseline in cellular NAD + levels. The only dose of NRPT that resulted in a statistically significant increase in whole blood NAD + levels at 48 h as compared to 0 h was 500 mg/100 mg in Step 2, yielding a 47% increase. The Step 3 dose resulted in a 67% increase in whole blood NAD + levels that was not statistically significant. Thus in retrospect, the initial goal of a 50 to 100% increase in NAD + levels was likely set too high, in large part because it was based on studies in healthy volunteers [ 10 , 11 ] without accounting for such a profound decrease in whole blood NAD + levels with kidney injury (50% decrease after 2 days of AKI). NR alone was previously tested at similar doses (100, 300 and 1000 mg) in a study of 12 healthy volunteers, resulting in a significant increase in peripheral blood mononuclear cell NAD + levels after 24 h (all NR doses combined) and no effect during earlier time points (1, 2, 4 and 8 h) [ 11 ]. The relative increase in NAD + at 24 h vs 0 h was 46% for both 300 mg and 1000 mg of NR and only 12% for 100 mg of NR. NAD + was not measured beyond 24 h in this study [ 11 ]. We now show, in patients with AKI, a comparable increase in NAD + levels (40% at 48 h vs 0 h in all Steps combined), but with delayed effect to 48 h. This could represent slower incline in cellular NAD + in patients with AKI or the effect of PT. We have previously tested the combination of NR and PT (NRPT 250 mg/50 mg and 500 mg/100 mg) in 120 elderly healthy volunteers, with the focus on NAD + levels at later time points, namely after 30 and 60 days of treatment [ 10 ]. After 30 days of treatment, whole blood NAD + levels in the healthy elderly population increased by 40% in NRPT 250/50 mg and 90% in NRPT 500/100 mg treatment groups and the effect was sustained until 60 days [ 10 ]. In our study, NRPT at the same doses in an AKI population increased whole blood NAD + levels by 23 and 47% respectively at 48 h.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","year":2025,"doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Yu 2025","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","year":2021,"doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Connell 2021","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_2","claim":"For instance, while one trial reported a trend toward improved NYHA class in heart failure patients [Yu 2025] [bundle:4], other trials in different populations found null effects on functional endpoints, such as mitochondrial respiration and skeletal muscle function in older adults [Connell 2021] [bundle:5] and cognition in long-COVID patients [Wu 2025] [bundle:1] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.1093/jn/nxab193] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633].","citation_support":[{"source_id":"source_1","study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","support_kind":"bundle_reference","cited_as":"Wu 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig."},{"source_id":"source_4","study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","support_kind":"bundle_reference","cited_as":"Yu 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115)."},{"source_id":"source_5","study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","support_kind":"bundle_reference","cited_as":"Connell 2021","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR"}],"candidate_sources":[]},{"claim_id":"claim_3","claim":"Null findings have a specific role in this evidence model. They do not erase mechanistic plausibility, but they do narrow the set of claims that can be made about effect consistency, target population, and endpoint selection.","citation_support":[],"candidate_sources":[{"study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","year":2025,"doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Wu 2025","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial","year":2025,"doi":"10.1002/lary.70173","url":"https://doi.org/10.1002/lary.70173","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Gao 2025","evidence_span":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p","excerpt":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p = 0.028). Tinnitus and aural fullness improved more in the NAD+ group, especially after 3 months.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","year":2020,"doi":"10.1186/s12882-020-02006-1","url":"https://doi.org/10.1186/s12882-020-02006-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Simic 2020","evidence_span":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was","excerpt":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD + response to treatment. Considering all Steps together, NRPT treatment increased NAD + levels by 37% at 48 h compared to 0 h ( p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. NRPT increases whole blood NAD + levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. NCT03176628 , date of registration June 5th, 2017. Keywords: Acute kidney injury, NAD + , Nicotinamide riboside, Pterostilbene, Safety study Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. AKI is most commonly diagnosed in patients following major invasive surgical procedures, in the setting of sepsis, or following administration of certain drugs or contrast dyes, particularly in patients with underlying hypertension, diabetes, or chronic kidney disease [ 1 ]. There is currently no specific treatment for AKI. Supportive measures include dialysis for patients with severe AKI, and mortality in this subset of patients exceeds 50% [ 2 ]. Thus, new preventive and treatment approaches are urgently needed. Nicotinamide adenine dinucleotide (NAD + ) is a key cellular factor linked to metabolism and longevity [ 3 ]. It is a required co-factor of SIRT1, a nuclear deacetylase that modulates chromatin structure, gene expression, extends lifespan in lower organisms, and improves many aging related diseases [ 4 , 5 ]. Experimental AKI in mice rapidly leads to the reduction of NAD + levels in the kidney that results from a combination of decreased NAD + biosynthesis and increased NAD + consumption [ 6 ]. NAD + augmentation by niacinamide has been shown to prevent various etiologies of experimental AKI in mice, and an initial pilot study has demonstrated the safety of niacinamide in patients undergoing cardiac surgery [ 7 ]. Further, mice deficient in SIRT1 are more susceptible to AKI and overexpression of SIRT1 protects from AKI [ 8 ]. These studies outline NAD + and SIRT1 modulation as a potential therapeutic approach in AKI [ 9 ]. Nicotinamide riboside with pterostilbene (NRPT) is a combination of nicotinamide riboside (NR), a form of vitamin B3, and pterostilbene (PT), a polyphenol found in blueberries [ 10 ]. NR is in wide use as an NAD + precursor, with distinct and superior pharmacokinetics to other NAD + intermediates in vitamin B metabolism such as nicotinic acid and niacinamide [ 11 ]. Through its effect on NAD + levels and SIRT1 activity, NR has been shown to have metabolic benefits and efficacy in a variety of disease models and to modestly increase lifespan in aged mice [ 12 ]. PT is a natural equivalent of the polyphenol resveratrol, an effective SIRT1 activator [ 13 ], that has greater bioavailability [ 14 ]. Therefore, the combination of NR and PT is predicted to have synergistic effect on metabolism, with NR augmenting NAD + levels and PT additionally activating SIRT1 [ 10 ]. NR supplementation alone has been studied in humans with cardiovascular [ 15 ], systemic metabolic [ 16 ], exercise [ 17 ], and muscle aging related end-points [ 18 ]. Further, NRPT has been evaluated in healthy elderly adults (age 60 to 80 years) and was shown to safely increase the blood concentration of NAD + in a dose-dependent manner by 40–90% [ 10 ]. To date, NR or NRPT have not been tested in patients with kidney disease. Thus, we sought to test the effect of escalating doses of NRPT on blood NAD+ levels and safety parameters in patients hospitalized with AKI, with the ultimate goal to test NRPT for the treatment of AKI. The incidence of AKI in hospitalized patients is about 1.6% with mortality rate of up to 35% [ 19 ]. AKI is associated with higher rates of death, subsequent hospitalization for stroke, heart failure, or myocardial infarction [ 20 ] and it accelerates the progression of CKD [ 21 ]. The management of patients with AKI is supportive, with renal replacement therapy indicated in patients with severe kidney injury. Currently, there are no specific therapeutics for the prevention and or management of AKI. Most studies in patients with AKI have focused on AKI after cardiac surgery, investigating renal perfusion, including studies investigating dopamine and neseritide, fenoldopam, aspirin or clonidine, buffered crystalloid, and remote ischemic preconditioning (reviewed in [ 22 ]), all to no avail. Trials examining the use of sodium bicarbonate or N-acetylcysteine in contrast induced nephropathy prevention have been inconclusive [ 23 ]. Because this prior focus on hemodynamics and perfusion has been unsuccessful, there has been increasing interest in augmenting kidney metabolic health by increasing NAD + levels and action as a novel therapeutic approach in AKI [ 7 , 9 ]. To our knowledge this is the first study describing whole blood NAD + levels in human AKI, with or without intervention. Across all treated individuals, NRPT treatment resulted in a significant increase in whole blood NAD + at 48 h. In placebo treated individuals, AKI resulted in a 50% decrease in whole blood NAD + levels at this time point. NRPT at all four tested doses was safe and well tolerated. These results motivate additional studies of NRPT as a potential therapeutic option in AKI. Our prespecified secondary endpoint was to determine the dose of NRPT that safely achieves at least a 50% increase (and up to a 100% increase) from baseline in cellular NAD + levels. The only dose of NRPT that resulted in a statistically significant increase in whole blood NAD + levels at 48 h as compared to 0 h was 500 mg/100 mg in Step 2, yielding a 47% increase. The Step 3 dose resulted in a 67% increase in whole blood NAD + levels that was not statistically significant. Thus in retrospect, the initial goal of a 50 to 100% increase in NAD + levels was likely set too high, in large part because it was based on studies in healthy volunteers [ 10 , 11 ] without accounting for such a profound decrease in whole blood NAD + levels with kidney injury (50% decrease after 2 days of AKI). NR alone was previously tested at similar doses (100, 300 and 1000 mg) in a study of 12 healthy volunteers, resulting in a significant increase in peripheral blood mononuclear cell NAD + levels after 24 h (all NR doses combined) and no effect during earlier time points (1, 2, 4 and 8 h) [ 11 ]. The relative increase in NAD + at 24 h vs 0 h was 46% for both 300 mg and 1000 mg of NR and only 12% for 100 mg of NR. NAD + was not measured beyond 24 h in this study [ 11 ]. We now show, in patients with AKI, a comparable increase in NAD + levels (40% at 48 h vs 0 h in all Steps combined), but with delayed effect to 48 h. This could represent slower incline in cellular NAD + in patients with AKI or the effect of PT. We have previously tested the combination of NR and PT (NRPT 250 mg/50 mg and 500 mg/100 mg) in 120 elderly healthy volunteers, with the focus on NAD + levels at later time points, namely after 30 and 60 days of treatment [ 10 ]. After 30 days of treatment, whole blood NAD + levels in the healthy elderly population increased by 40% in NRPT 250/50 mg and 90% in NRPT 500/100 mg treatment groups and the effect was sustained until 60 days [ 10 ]. In our study, NRPT at the same doses in an AKI population increased whole blood NAD + levels by 23 and 47% respectively at 48 h.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","year":2025,"doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Yu 2025","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","year":2021,"doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Connell 2021","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_4","claim":"For instance, while one trial reported a trend toward improved NYHA class in heart failure patients [Yu 2025] [bundle:4], other trials in different populations found null effects on functional endpoints, such as mitochondrial respiration and skeletal muscle function in older adults [Connell 2021] [bundle:5] and cognition in long-COVID patients [Wu 2025] [bundle:1] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.1093/jn/nxab193] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633].","citation_support":[{"source_id":"source_1","study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","support_kind":"bundle_reference","cited_as":"Wu 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig."},{"source_id":"source_4","study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","support_kind":"bundle_reference","cited_as":"Yu 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115)."},{"source_id":"source_5","study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","support_kind":"bundle_reference","cited_as":"Connell 2021","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR"}],"candidate_sources":[]},{"claim_id":"claim_5","claim":"The geroscience framework reframes the clinical challenge: rather than developing separate therapies for heart failure, atherosclerosis, and metabolic syndrome, one might target the shared biological substrate of aging itself. NAD+ precursors, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), represent a drug class that has moved rapidly from preclinical observation to human supplementation trials. The regulatory pathway for these compounds has been complex; they are often marketed as dietary supplements, which permits consumer access but limits the regulatory oversight and standardized dosing that characterize pharmaceutical development. Another trial demonstrated that a combination of nicotinamide and D-ribose (RiaGev) increased the NAD+ metabolome, with NADP+ rising by 27% compared to placebo after seven days of supplementation [Xue 2022] [bundle:7] [exact source: https://doi.org/10.3390/nu14112219]. These findings confirm that oral precursors can reliably raise circulating NAD+, but the critical question is whether this biochemical elevation translates into clinically meaningful cardiovascular protection.","citation_support":[{"source_id":"source_7","study":"A Combination of Nicotinamide and D-Ribose (RiaGev) Is Safe and Effective to Increase NAD + Metabolome in Healthy Middle-Aged Adults: A Randomized, Triple-Blind, Placebo-Controlled, Cross-Over Pilot Clinical Trial","doi":"10.3390/nu14112219","url":"https://doi.org/10.3390/nu14112219","support_kind":"bundle_reference","cited_as":"Xue 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"Supplementing with 1520 mg RiaGev twice daily for 7 days significantly increased the NAD + metabolome in blood, especially NADP + by 27% compared to the placebo group ( p = 0.033) and over the baseline ( p = 0.007). Increases in glutathione and high energy phosphates were also observed in the blood. Seven-day supplementation with RiaGev significantly ( p = 0.013) reduced overall blood glucose without significant changes in insulin secretion ( p = 0.796), suggesting an improved insulin sensitivity and glucose tolerance. The waking salivary cortisol of the subjects steadily and significantly","excerpt":"Supplementing with 1520 mg RiaGev twice daily for 7 days significantly increased the NAD + metabolome in blood, especially NADP + by 27% compared to the placebo group ( p = 0.033) and over the baseline ( p = 0.007). Increases in glutathione and high energy phosphates were also observed in the blood. Seven-day supplementation with RiaGev significantly ( p = 0.013) reduced overall blood glucose without significant changes in insulin secretion ( p = 0.796), suggesting an improved insulin sensitivity and glucose tolerance. The waking salivary cortisol of the subjects steadily and significantly decreased ( p = 0.026) in the RiaGev group in contrast to the placebo."}],"candidate_sources":[]},{"claim_id":"claim_6","claim":"A review of the human RCT landscape reveals a striking heterogeneity in study populations, interventions, and endpoints, with very few trials directly assessing cardiovascular outcomes. The most direct cardiovascular evidence comes from a trial in patients with heart failure caused by ischemic cardiomyopathy, where intravenous NAD+ was compared to placebo. This study reported a statistically significant improvement in left ventricular ejection fraction (LVEF) within the NAD+ group at one month, but the between-group comparison for New York Heart Association (NYHA) class improvement showed only a trend (P = 0.088 at one month, P = 0.115 at six months) [Yu 2025] [bundle:4] [exact source: https://doi.org/10.1007/s40256-025-00764-7]. A separate trial in older adults with heart failure found that seven days of intravenous NAD+ injection improved NT-proBNP levels and LVEF values compared to saline, although the differences were not statistically significant [Pei 2024] [bundle:11] [exact source: https://doi.org/10.31083/j.rcm2508297]. Other trials have examined NAD+ precursors in populations with acute kidney injury [Simic 2020 [bundle:3], Pencina 2025 [bundle:12]], long-COVID [Wu 2025] [bundle:1], sudden sensorineural hearing loss [Gao 2025] [bundle:2], and mild cognitive impairment [Roy 2026] [bundle:9], where cardiovascular endpoints were not the primary focus [exact source: https://doi.org/10.1186/s12882-020-02006-1] [exact source: https://doi.org/10.1096/fba.2025-00014] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633] [exact source: https://doi.org/10.1002/lary.70173] [exact source: https://doi.org/10.1002/trc2.70278]. This fragmentation of the evidence base means that any synthesis of cardiovascular effects must draw indirect inferences from trials designed for other purposes.","citation_support":[{"source_id":"source_1","study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","support_kind":"bundle_reference","cited_as":"Wu 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig."},{"source_id":"source_2","study":"NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial","doi":"10.1002/lary.70173","url":"https://doi.org/10.1002/lary.70173","support_kind":"bundle_reference","cited_as":"Gao 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p","excerpt":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p = 0.028). Tinnitus and aural fullness improved more in the NAD+ group, especially after 3 months."},{"source_id":"source_3","study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","doi":"10.1186/s12882-020-02006-1","url":"https://doi.org/10.1186/s12882-020-02006-1","support_kind":"bundle_reference","cited_as":"Simic 2020","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was","excerpt":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD + response to treatment. Considering all Steps together, NRPT treatment increased NAD + levels by 37% at 48 h compared to 0 h ( p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. NRPT increases whole blood NAD + levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. NCT03176628 , date of registration June 5th, 2017. Keywords: Acute kidney injury, NAD + , Nicotinamide riboside, Pterostilbene, Safety study Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. AKI is most commonly diagnosed in patients following major invasive surgical procedures, in the setting of sepsis, or following administration of certain drugs or contrast dyes, particularly in patients with underlying hypertension, diabetes, or chronic kidney disease [ 1 ]. There is currently no specific treatment for AKI. Supportive measures include dialysis for patients with severe AKI, and mortality in this subset of patients exceeds 50% [ 2 ]. Thus, new preventive and treatment approaches are urgently needed. Nicotinamide adenine dinucleotide (NAD + ) is a key cellular factor linked to metabolism and longevity [ 3 ]. It is a required co-factor of SIRT1, a nuclear deacetylase that modulates chromatin structure, gene expression, extends lifespan in lower organisms, and improves many aging related diseases [ 4 , 5 ]. Experimental AKI in mice rapidly leads to the reduction of NAD + levels in the kidney that results from a combination of decreased NAD + biosynthesis and increased NAD + consumption [ 6 ]. NAD + augmentation by niacinamide has been shown to prevent various etiologies of experimental AKI in mice, and an initial pilot study has demonstrated the safety of niacinamide in patients undergoing cardiac surgery [ 7 ]. Further, mice deficient in SIRT1 are more susceptible to AKI and overexpression of SIRT1 protects from AKI [ 8 ]. These studies outline NAD + and SIRT1 modulation as a potential therapeutic approach in AKI [ 9 ]. Nicotinamide riboside with pterostilbene (NRPT) is a combination of nicotinamide riboside (NR), a form of vitamin B3, and pterostilbene (PT), a polyphenol found in blueberries [ 10 ]. NR is in wide use as an NAD + precursor, with distinct and superior pharmacokinetics to other NAD + intermediates in vitamin B metabolism such as nicotinic acid and niacinamide [ 11 ]. Through its effect on NAD + levels and SIRT1 activity, NR has been shown to have metabolic benefits and efficacy in a variety of disease models and to modestly increase lifespan in aged mice [ 12 ]. PT is a natural equivalent of the polyphenol resveratrol, an effective SIRT1 activator [ 13 ], that has greater bioavailability [ 14 ]. Therefore, the combination of NR and PT is predicted to have synergistic effect on metabolism, with NR augmenting NAD + levels and PT additionally activating SIRT1 [ 10 ]. NR supplementation alone has been studied in humans with cardiovascular [ 15 ], systemic metabolic [ 16 ], exercise [ 17 ], and muscle aging related end-points [ 18 ]. Further, NRPT has been evaluated in healthy elderly adults (age 60 to 80 years) and was shown to safely increase the blood concentration of NAD + in a dose-dependent manner by 40–90% [ 10 ]. To date, NR or NRPT have not been tested in patients with kidney disease. Thus, we sought to test the effect of escalating doses of NRPT on blood NAD+ levels and safety parameters in patients hospitalized with AKI, with the ultimate goal to test NRPT for the treatment of AKI. The incidence of AKI in hospitalized patients is about 1.6% with mortality rate of up to 35% [ 19 ]. AKI is associated with higher rates of death, subsequent hospitalization for stroke, heart failure, or myocardial infarction [ 20 ] and it accelerates the progression of CKD [ 21 ]. The management of patients with AKI is supportive, with renal replacement therapy indicated in patients with severe kidney injury. Currently, there are no specific therapeutics for the prevention and or management of AKI. Most studies in patients with AKI have focused on AKI after cardiac surgery, investigating renal perfusion, including studies investigating dopamine and neseritide, fenoldopam, aspirin or clonidine, buffered crystalloid, and remote ischemic preconditioning (reviewed in [ 22 ]), all to no avail. Trials examining the use of sodium bicarbonate or N-acetylcysteine in contrast induced nephropathy prevention have been inconclusive [ 23 ]. Because this prior focus on hemodynamics and perfusion has been unsuccessful, there has been increasing interest in augmenting kidney metabolic health by increasing NAD + levels and action as a novel therapeutic approach in AKI [ 7 , 9 ]. To our knowledge this is the first study describing whole blood NAD + levels in human AKI, with or without intervention. Across all treated individuals, NRPT treatment resulted in a significant increase in whole blood NAD + at 48 h. In placebo treated individuals, AKI resulted in a 50% decrease in whole blood NAD + levels at this time point. NRPT at all four tested doses was safe and well tolerated. These results motivate additional studies of NRPT as a potential therapeutic option in AKI. Our prespecified secondary endpoint was to determine the dose of NRPT that safely achieves at least a 50% increase (and up to a 100% increase) from baseline in cellular NAD + levels. The only dose of NRPT that resulted in a statistically significant increase in whole blood NAD + levels at 48 h as compared to 0 h was 500 mg/100 mg in Step 2, yielding a 47% increase. The Step 3 dose resulted in a 67% increase in whole blood NAD + levels that was not statistically significant. Thus in retrospect, the initial goal of a 50 to 100% increase in NAD + levels was likely set too high, in large part because it was based on studies in healthy volunteers [ 10 , 11 ] without accounting for such a profound decrease in whole blood NAD + levels with kidney injury (50% decrease after 2 days of AKI). NR alone was previously tested at similar doses (100, 300 and 1000 mg) in a study of 12 healthy volunteers, resulting in a significant increase in peripheral blood mononuclear cell NAD + levels after 24 h (all NR doses combined) and no effect during earlier time points (1, 2, 4 and 8 h) [ 11 ]. The relative increase in NAD + at 24 h vs 0 h was 46% for both 300 mg and 1000 mg of NR and only 12% for 100 mg of NR. NAD + was not measured beyond 24 h in this study [ 11 ]. We now show, in patients with AKI, a comparable increase in NAD + levels (40% at 48 h vs 0 h in all Steps combined), but with delayed effect to 48 h. This could represent slower incline in cellular NAD + in patients with AKI or the effect of PT. We have previously tested the combination of NR and PT (NRPT 250 mg/50 mg and 500 mg/100 mg) in 120 elderly healthy volunteers, with the focus on NAD + levels at later time points, namely after 30 and 60 days of treatment [ 10 ]. After 30 days of treatment, whole blood NAD + levels in the healthy elderly population increased by 40% in NRPT 250/50 mg and 90% in NRPT 500/100 mg treatment groups and the effect was sustained until 60 days [ 10 ]. In our study, NRPT at the same doses in an AKI population increased whole blood NAD + levels by 23 and 47% respectively at 48 h."},{"source_id":"source_4","study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","support_kind":"bundle_reference","cited_as":"Yu 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115)."},{"source_id":"source_11","study":"Effects of Nicotinamide Adenine Dinucleotide on Older Patients with Heart Failure","doi":"10.31083/j.rcm2508297","url":"https://doi.org/10.31083/j.rcm2508297","support_kind":"bundle_reference","cited_as":"Pei 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"Based on using conventional drugs to treat HF, patients (n = 60) were randomized 1:1 to saline and 50 mg NAD + with 50 mL of normal saline for 7 days. The baseline characteristics of patients before and after treatment and cardiac function (N-terminal pro B-type natriuretic peptide (NT-proBNP) level and left ventricular ejection fraction (LVEF) value) were analyzed. Serological analysis (sirtuin-1 (SIRT1), sirtuin-3 (SIRT3), sirtuin-6 (SIRT6), reactive oxygen species (ROS), and endothelin) was also performed. Among the 60 patients with HF who were treated with NAD + for 7 days, the","excerpt":"Based on using conventional drugs to treat HF, patients (n = 60) were randomized 1:1 to saline and 50 mg NAD + with 50 mL of normal saline for 7 days. The baseline characteristics of patients before and after treatment and cardiac function (N-terminal pro B-type natriuretic peptide (NT-proBNP) level and left ventricular ejection fraction (LVEF) value) were analyzed. Serological analysis (sirtuin-1 (SIRT1), sirtuin-3 (SIRT3), sirtuin-6 (SIRT6), reactive oxygen species (ROS), and endothelin) was also performed. Among the 60 patients with HF who were treated with NAD + for 7 days, the improvement rate in NT-proBNP levels and LVEF values was better than in the saline group, although not statistically significant. These patients were more likely to benefit from NAD + because of higher levels of anti-oxidative stress (SIRT1, SIRT3, SIRT6, and ROS) and anti-endothelial injury (endothelin) than those in the saline control group. According to the results of this study, it is believed that 7 days of NAD + injections has a positive effect on improving cardiac function, oxidative stress, and endothelial injury in patients with HF compared with the saline control. Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ ) ChiCTR2300074326; retrospectively registered on 3 August 2023. Keywords: heart failure, NAD + , clinical study, adjuvant therapy Heart failure (HF) poses a serious threat to human health and is characterized by high morbidity, high mortality, a high rehospitalization rate, and many high-risk groups. The American Heart Association/American College of Cardiology guidelines define HF as “a complex clinical syndrome caused by any structural or functional heart disease that affects the ability of the ventricles to fill and shoot blood” [ 1 ]. Benjamin et al . [ 2 ] reported that patients hospitalized for HF are at an increased risk of HF rehospitalization and cardiovascular death. One in eight deaths is due to HF, and the mortality rate within 5 years of diagnosis is as high as 50%, exceeding that of some malignancies [ 2 ]. Despite the increased number of drugs used to treat HF, the fatality rate remains high. The 2021 European Society of Cardiology guidelines recommend a combination of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin-receptor neprilysin inhibitor, β -blockers, and aldosterone receptor antagonists (MRAs) as the primary treatment for chronic HF [ 3 ]. Both the previous “golden triangle” ( β -blocker, ACEI/angiotensin II receptor blocker [ARB], and MRA) and the current “five golden flowers” ( β -blocker, ACEI/ARB, MRA, and sodium-dependent glucose transporter 2 inhibitors) have limitations in clinical treatment [ 4 , 5 , 6 ]. Current drug therapy still cannot meet the needs of HF management, making it necessary to develop new treatment ideas and explore new treatment strategies. Nicotinamide adenine dinucleotide (NAD + ) is an important cofactor and a key metabolic enzyme substrate involved in redox reactions in the mitochondria, which is greatly significant in maintaining the balance of NAD + in vivo for normal human metabolism [ 7 ]. Several studies have shown that NAD + can inhibit inflammation and oxidative stress injury in endothelial cells, reduce apoptosis in microvascular endothelial cells, promote microangiogenesis, and improve microvascular injury caused by coronary microcirculation and myocardial ischemia-reperfusion [ 8 ]. Studies have also shown that the NAD + concentration in the blood of patients with HF is significantly lower than in healthy people, and with an increase in age, NAD + also has a trend of gradually decreasing [ 7 , 9 ]. Therefore, stabilizing intracellular NAD + levels through exogenous NAD + supplementation is expected to be a therapeutic strategy for improving cardiac bioenergetics and function. HF is the leading cause of hospitalization among older populations worldwide, with a high mortality rate and impact on the quality of life of patients [ 10 , 11 ]. With the development of medical technology, various drugs have emerged to treat HF. However, the effectiveness of these drugs remains unsatisfactory. HF remains an intractable disease, with an increased burden of hospitalization and a continuous loss of health care expenditure [ 12 ]. Therefore, it is necessary to identify alternative and complementary treatment options. Thus, we sought to evaluate whether NAD + therapy has some clinical efficacy in patients with HF. NAD + is widely present in the mitochondria of myocardial tissue, and NAD + activates the deacetylation activity of sirtuins, regulates the activity of numerous aging-related transcription factors, and intervenes in aging and aging-related diseases [ 9 , 13 , 14 ]. Several studies have shown that NAD + has beneficial effects on cardiovascular diseases by regulating metabolism, maintaining redox homeostasis, and modulating immune responses [ 15 , 16 , 17 ]. Studies have found that NAD + levels are significantly reduced in patients with HF [ 18 , 19 ]. In a rat model of myocardial infarction, compared with the LCZ696-positive drug control group, using NAD + improved some cardiac function and hemodynamic indexes and could further increase the left ventricular stroke output and systolic and diastolic blood pressure [ 20 ]. In the present clinical trial, we tested whether using exogenous NAD + supplementation as a new adjuvant treatment for HF is possible. NT-proBNP and LVEF are the most widely used laboratory indices for evaluating HF severity and prognosis. In our clinical trial, NT-proBNP levels improved in both groups, possibly because patients in both groups were rigorously treated with anti-HF drugs. However, the improvement was more obvious in the NAD + group than in the saline control group, which better reflects that the therapeutic effect of NAD + in patients with HF is independent of conventional medication for HF. Although the NT-proBNP level in the NAD + group improved from baseline, no statistically significant difference was found over time. This finding may be due to the large dispersion of the data, short treatment course, and small sample size; similarly, due to short-term drug use, changes in the structure and function of the heart cannot be obvious over a short time. Moreover, the measurement of LVEF is subjective to a certain extent and is related to the experience of the tester. LVEF in the NAD + group was improved, with no statistical difference between the groups. Studies have found that women may have lower NAD + concentrations and benefit most from improved heart function [ 21 , 22 ]. In our study, there was no statistical difference in gender between the two groups of patients, and whether women can benefit more from NAD + treatment will be our major direction in the future. Oxidative stress plays an important role in HF occurrence and progression [ 23 ]. The sirtuin family is also linked to several antioxidant and oxidative stress-related processes and functions [ 24 ]. Sirtuins are a family of seven enzymes (sirtuin1–7) involved in regulating many metabolic processes [ 25 ]. Sirtuin agonists are more convincing than existing deacetylase inhibitors for the treatment of cardiovascular diseases in terms of safety and efficacy and may have clinical value for treating multiple types of cardiovascular diseases [ 26 ]. Increasing the NAD + level in vivo can activate sirtuins, which can significantly inhibit myocardial hyperacetylation and improve myocardial mitochondrial function [ 27 ]. Clemency et al . [ 28 ] found that sodium-glucose cotransporter 2 (SGL-2) inhibitor could inhibit oxidative stress by increasing the expression of SIRT1 and SIRT3 and decreasing the expression of SIRT6, thereby alleviating myocardial injury. In our clinical trial, the SIRT1, SIRT3, and SIRT6 levels increased at the 2-week follow-up after medication, but over time, the concentration of exogenous supplemental NAD + gradually decreased in vivo and showed a trend of gradual decrease in the last two follow-up visits, which is also consistent with the metabolic process of intravenous drug use in the body. Furthermore, there was an interaction between SIRT1 in the saline control group and the NAD + group, which confirmed that NAD + plays a critical role in anti-oxidative stress. We observed that ROS levels increased in the NAD + group at the 2-week follow-up visit, possibly due to the negative feedback reaction of inflammation caused by the strong antioxidant effect in the short term. However, those levels improved at later visits. Increased levels of ET, the most potent vasoconstrictor, are produced by the pro-peptide precursor, large ET, through ET convertase [ 29 ]. ET in the peripheral blood of patients with HF can predict poor prognosis [ 30 , 31 , 32 ]. In this clinical trial, there were significant differences in ET levels between the saline control and NAD + groups, which confirmed that NAD + plays a more critical role in anti-endothelial injury. Although there was no difference in the incidence of composite endpoint events (including all-cause death and readmission due to HF) during the 1-year follow-up period in this study, there was still a significant difference in mortality between the two groups. The survival rate of NAD + was higher, and most patients who died were in the saline control group, usually 2–4 months after treatment. These results suggest that the use of NAD + may delay the progression of HF and reduce short-term mortality. The reason why no statistical difference was found in the various clinical endpoints in this study may be related to the small number of study cases, the short duration of NAD + administration, and the short follow-up time. Nevertheless, this study has expanded our ideas for exploring new treatments for patients with HF and confirmed their therapeutic effect on patients with HF based on molecular biology and echocardiography evaluation indicators. We also expect this study’s results to guide follow-up national multicenter, large-sample, prospective, randomized, double-blind controlled studies. We further confirmed the therapeutic effects of NAD + in the HF population. According to the product instructions, NAD + occasionally has side effects such as dry mouth, nausea, dizziness, and palpitations. However, in this clinical trial, patients had no obvious complaints after 7 days of intravenously administering NAD + , but the long-term effect or safety of treatment still needs to be observed over a longer study period. In addition, the follow-up of participants after completing this clinical trial may be limited, making it difficult to assess long-term outcomes and treatment safety. Our study consisted of a small sample size from a single center, potentially limiting the generalizability of our findings to a broader population of HF patients. Future multicenter studies covering cohorts with different demographic and clinical characteristics would help validate our findings and enhance external validity. In addition, we did not perform cardiovascular magnetic resonance to assess patients with HF more comprehensively. We did not discuss the pharmacological background of HF patients further, and our future research direction will be to focus on their pharmacological background. Among patients with HF, those injected with NAD + for 7 days may benefit more from improved cardiac function, levels of anti-oxidative stress, and endothelial injury than those re"},{"source_id":"source_12","study":"Oral MIB‐626 (β Nicotinamide Mononucleotide) Safely Raises Blood Nicotinamide Adenine Dinucleotide Levels in Hospitalized Patients With COVID‐19 and Acute Kidney Injury: A Randomized Controlled Trial","doi":"10.1096/fba.2025-00014","url":"https://doi.org/10.1096/fba.2025-00014","support_kind":"bundle_reference","cited_as":"Pencina 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"To determine whether MIB‐626 ( β‐ nicotinamide mononucleotide), an NAD + precursor, can safely increase blood NAD + levels and attenuate acute kidney injury (AKI) and inflammation in hospitalized patients with COVID‐19, 42 adults, ≥ 18 years, hospitalized with COVID‐19 and AKI, were randomized in a 3:2 ratio to MIB‐626 1.0‐g or placebo tablets twice daily for 14 days. Circulating NAD + and its metabolites, markers of AKI, inflammation, and disease severity, were assessed. MIB‐626 treatment significantly but gradually raised blood NAD + levels to a peak between 5 to 14 days (16.0 ± 6.9, 25.5 ±","excerpt":"To determine whether MIB‐626 ( β‐ nicotinamide mononucleotide), an NAD + precursor, can safely increase blood NAD + levels and attenuate acute kidney injury (AKI) and inflammation in hospitalized patients with COVID‐19, 42 adults, ≥ 18 years, hospitalized with COVID‐19 and AKI, were randomized in a 3:2 ratio to MIB‐626 1.0‐g or placebo tablets twice daily for 14 days. Circulating NAD + and its metabolites, markers of AKI, inflammation, and disease severity, were assessed. MIB‐626 treatment significantly but gradually raised blood NAD + levels to a peak between 5 to 14 days (16.0 ± 6.9, 25.5 ± 12.6, and 42.6 ± 25.6 μg/mL at baseline, days 5 and 14) and raised plasma concentrations of NAD + metabolites 1‐methylnicotinamide, N‐methyl, 2‐pyridone, 4‐carboxamide rapidly to a peak by day 3. Changes in serum creatinine, cystatin‐C, and serum markers of AKI did not differ significantly between groups. Serum CRP, IL‐6, and TNFα and indices of disease severity also did not differ between groups. MIB‐626 treatment of patients with COVID‐19 and AKI safely and substantially raised blood NAD + and plasma concentrations of NAD + metabolites. Markers of AKI, inflammation, and disease severity did not differ between groups, likely due to the slow rise in NAD + levels. Future studies should assess whether a rapid increase in NAD + by parenteral administration can attenuate disease severity and AKI. Trial Registration: ClinicalTrials.gov Identifier: NCT05038488 Keywords: acute kidney injury, COVID‐19, NAD augmentation, NAD metabolism, NAD precursor, nicotinamide mononucleotide This placebo‐controlled, randomized, parallel group, double‐blind trial was conducted at 3 trial sites: Brigham and Women's Hospital in Boston, MA; University of Texas Medical Branch, Galveston, TX; and Tulane University Medical Center, New Orleans, LA. The study protocol was approved by the trial's single institutional review board (sIRB) at the Mass General Brigham Human Research Protection Program and the institutional review boards of the participating trial sites ceded to the sIRB. An independent Data and Safety Monitoring Board (DSMB) reviewed the safety data and study progress every 6 weeks to 3 months. The participants provided consent and authorization for the use and disclosure of personal health information in accordance with the Health Insurance Portability and Accountability Act. The trial was registered at ClinicalTrials.gov . This is the first randomized, placebo‐controlled trial of NAD + augmentation in patients hospitalized with moderately severe SARS‐CoV‐2 infection to show that MIB‐626 was safe, well tolerated, and efficacious in raising blood NAD + levels in patients with COVID‐19. The present study also shows that blood NAD + levels are only modestly lower in patients with COVID‐19 compared to healthy adults without COVID‐19 but that the circulating concentrations of NAD + metabolites such as MeNAM, NAM, and 2‐PY are markedly increased in patients with COVID‐19 compared with healthy adults, suggesting increased turnover of NAD + due to marked upregulation of enzymes involved in NAD consumption as well as synthesis, as suggested by our previous observational study of patients with COVID‐19 [ 16 ]. In spite of the increased NAD + turnover during acute COVID‐19, the MIB‐626 regimen used in this study (1.0 g twice daily) significantly raised NAD + levels, although the increment above baseline was lower than that observed in our previous studies in healthy adults with a similar dose regimen [ 18 , 19 ]. Consistent with our previous phase 1 studies [ 18 , 19 ], blood NAD + levels rose gradually in MIB‐626‐treated patients and reached the peak steady state levels between days 5 and 14, even though the plasma levels of its metabolites, MeNAM and 2‐PY, reached peak levels by day 3, which was the earliest sampling time point after randomization. The reasons for the slow ramp up of blood NAD + levels in spite of a more rapid increase in circulating levels of its metabolites after oral NMN administration are not clear. It is possible that a longer time period is required to reach peak steady state levels due to the substantially increased NAD + turnover in patients with COVID‐19. The mechanisms by which oral NAD + precursors, NMN and NR, increase blood and tissue NAD + levels need further investigation by metabolic flux studies using stable isotope‐labeled NAD + precursors. This relatively small trial did not reveal significant differences in serum creatinine or cystatin C or other serum markers of acute kidney injury, or in other clinical indices of disease severity. Due to the small sample size and substantial variability in the study's clinical endpoints in acutely ill patients with multiple comorbidities, the study likely did not have sufficient statistical power to detect meaningful differences in these endpoints. It took more than 5 days to achieve peak NAD + levels by which time, many patients had been discharged and this may have obscured the drug's efficacy."}],"candidate_sources":[]},{"claim_id":"claim_7","claim":"Several unresolved questions complicate the interpretation of the existing evidence. First, the mechanism by which elevated NAD+ might improve cardiac function remains poorly defined in humans; proposed pathways include enhanced mitochondrial bioenergetics, reduced oxidative stress, and improved endothelial function, but these are largely extrapolated from preclinical models. Second, the duration of supplementation in most trials is short—often weeks to a few months—raising the question of whether longer-term exposure is necessary for cardiovascular benefit or whether it introduces unforeseen risks. Third, dose-response relationships are unclear; trials have used a wide range of doses, from 250 mg/day of NMN [Katayoshi 2023] [bundle:10] to 1000 mg twice daily of NR [Airhart 2017] [bundle:15], and the optimal dose for cardiovascular protection is unknown [exact source: https://doi.org/10.1038/s41598-023-29787-3] [exact source: https://doi.org/10.1371/journal.pone.0186459]. Fourth, population specificity is a concern, as the most promising cardiovascular signals come from patients with established heart failure [Yu 2025 [bundle:4], Pei 2024 [bundle:11]], while trials in healthier populations have not demonstrated clear cardiovascular benefits [Martens 2018] [bundle:16] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.31083/j.rcm2508297] [exact source: https://doi.org/10.1038/s41467-018-03421-7]. Finally, the trade-off between potential benefits and safety in vulnerable populations, such as those with acute kidney injury, requires careful evaluation [Simic 2020 [bundle:3], Pencina 2025 [bundle:12]] [exact source: https://doi.org/10.1186/s12882-020-02006-1] [exact source: https://doi.org/10.1096/fba.2025-00014].","citation_support":[{"source_id":"source_3","study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","doi":"10.1186/s12882-020-02006-1","url":"https://doi.org/10.1186/s12882-020-02006-1","support_kind":"bundle_reference","cited_as":"Simic 2020","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was","excerpt":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD + response to treatment. Considering all Steps together, NRPT treatment increased NAD + levels by 37% at 48 h compared to 0 h ( p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. NRPT increases whole blood NAD + levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. NCT03176628 , date of registration June 5th, 2017. Keywords: Acute kidney injury, NAD + , Nicotinamide riboside, Pterostilbene, Safety study Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. AKI is most commonly diagnosed in patients following major invasive surgical procedures, in the setting of sepsis, or following administration of certain drugs or contrast dyes, particularly in patients with underlying hypertension, diabetes, or chronic kidney disease [ 1 ]. There is currently no specific treatment for AKI. Supportive measures include dialysis for patients with severe AKI, and mortality in this subset of patients exceeds 50% [ 2 ]. Thus, new preventive and treatment approaches are urgently needed. Nicotinamide adenine dinucleotide (NAD + ) is a key cellular factor linked to metabolism and longevity [ 3 ]. It is a required co-factor of SIRT1, a nuclear deacetylase that modulates chromatin structure, gene expression, extends lifespan in lower organisms, and improves many aging related diseases [ 4 , 5 ]. Experimental AKI in mice rapidly leads to the reduction of NAD + levels in the kidney that results from a combination of decreased NAD + biosynthesis and increased NAD + consumption [ 6 ]. NAD + augmentation by niacinamide has been shown to prevent various etiologies of experimental AKI in mice, and an initial pilot study has demonstrated the safety of niacinamide in patients undergoing cardiac surgery [ 7 ]. Further, mice deficient in SIRT1 are more susceptible to AKI and overexpression of SIRT1 protects from AKI [ 8 ]. These studies outline NAD + and SIRT1 modulation as a potential therapeutic approach in AKI [ 9 ]. Nicotinamide riboside with pterostilbene (NRPT) is a combination of nicotinamide riboside (NR), a form of vitamin B3, and pterostilbene (PT), a polyphenol found in blueberries [ 10 ]. NR is in wide use as an NAD + precursor, with distinct and superior pharmacokinetics to other NAD + intermediates in vitamin B metabolism such as nicotinic acid and niacinamide [ 11 ]. Through its effect on NAD + levels and SIRT1 activity, NR has been shown to have metabolic benefits and efficacy in a variety of disease models and to modestly increase lifespan in aged mice [ 12 ]. PT is a natural equivalent of the polyphenol resveratrol, an effective SIRT1 activator [ 13 ], that has greater bioavailability [ 14 ]. Therefore, the combination of NR and PT is predicted to have synergistic effect on metabolism, with NR augmenting NAD + levels and PT additionally activating SIRT1 [ 10 ]. NR supplementation alone has been studied in humans with cardiovascular [ 15 ], systemic metabolic [ 16 ], exercise [ 17 ], and muscle aging related end-points [ 18 ]. Further, NRPT has been evaluated in healthy elderly adults (age 60 to 80 years) and was shown to safely increase the blood concentration of NAD + in a dose-dependent manner by 40–90% [ 10 ]. To date, NR or NRPT have not been tested in patients with kidney disease. Thus, we sought to test the effect of escalating doses of NRPT on blood NAD+ levels and safety parameters in patients hospitalized with AKI, with the ultimate goal to test NRPT for the treatment of AKI. The incidence of AKI in hospitalized patients is about 1.6% with mortality rate of up to 35% [ 19 ]. AKI is associated with higher rates of death, subsequent hospitalization for stroke, heart failure, or myocardial infarction [ 20 ] and it accelerates the progression of CKD [ 21 ]. The management of patients with AKI is supportive, with renal replacement therapy indicated in patients with severe kidney injury. Currently, there are no specific therapeutics for the prevention and or management of AKI. Most studies in patients with AKI have focused on AKI after cardiac surgery, investigating renal perfusion, including studies investigating dopamine and neseritide, fenoldopam, aspirin or clonidine, buffered crystalloid, and remote ischemic preconditioning (reviewed in [ 22 ]), all to no avail. Trials examining the use of sodium bicarbonate or N-acetylcysteine in contrast induced nephropathy prevention have been inconclusive [ 23 ]. Because this prior focus on hemodynamics and perfusion has been unsuccessful, there has been increasing interest in augmenting kidney metabolic health by increasing NAD + levels and action as a novel therapeutic approach in AKI [ 7 , 9 ]. To our knowledge this is the first study describing whole blood NAD + levels in human AKI, with or without intervention. Across all treated individuals, NRPT treatment resulted in a significant increase in whole blood NAD + at 48 h. In placebo treated individuals, AKI resulted in a 50% decrease in whole blood NAD + levels at this time point. NRPT at all four tested doses was safe and well tolerated. These results motivate additional studies of NRPT as a potential therapeutic option in AKI. Our prespecified secondary endpoint was to determine the dose of NRPT that safely achieves at least a 50% increase (and up to a 100% increase) from baseline in cellular NAD + levels. The only dose of NRPT that resulted in a statistically significant increase in whole blood NAD + levels at 48 h as compared to 0 h was 500 mg/100 mg in Step 2, yielding a 47% increase. The Step 3 dose resulted in a 67% increase in whole blood NAD + levels that was not statistically significant. Thus in retrospect, the initial goal of a 50 to 100% increase in NAD + levels was likely set too high, in large part because it was based on studies in healthy volunteers [ 10 , 11 ] without accounting for such a profound decrease in whole blood NAD + levels with kidney injury (50% decrease after 2 days of AKI). NR alone was previously tested at similar doses (100, 300 and 1000 mg) in a study of 12 healthy volunteers, resulting in a significant increase in peripheral blood mononuclear cell NAD + levels after 24 h (all NR doses combined) and no effect during earlier time points (1, 2, 4 and 8 h) [ 11 ]. The relative increase in NAD + at 24 h vs 0 h was 46% for both 300 mg and 1000 mg of NR and only 12% for 100 mg of NR. NAD + was not measured beyond 24 h in this study [ 11 ]. We now show, in patients with AKI, a comparable increase in NAD + levels (40% at 48 h vs 0 h in all Steps combined), but with delayed effect to 48 h. This could represent slower incline in cellular NAD + in patients with AKI or the effect of PT. We have previously tested the combination of NR and PT (NRPT 250 mg/50 mg and 500 mg/100 mg) in 120 elderly healthy volunteers, with the focus on NAD + levels at later time points, namely after 30 and 60 days of treatment [ 10 ]. After 30 days of treatment, whole blood NAD + levels in the healthy elderly population increased by 40% in NRPT 250/50 mg and 90% in NRPT 500/100 mg treatment groups and the effect was sustained until 60 days [ 10 ]. In our study, NRPT at the same doses in an AKI population increased whole blood NAD + levels by 23 and 47% respectively at 48 h."},{"source_id":"source_4","study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","support_kind":"bundle_reference","cited_as":"Yu 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115)."},{"source_id":"source_11","study":"Effects of Nicotinamide Adenine Dinucleotide on Older Patients with Heart Failure","doi":"10.31083/j.rcm2508297","url":"https://doi.org/10.31083/j.rcm2508297","support_kind":"bundle_reference","cited_as":"Pei 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"Based on using conventional drugs to treat HF, patients (n = 60) were randomized 1:1 to saline and 50 mg NAD + with 50 mL of normal saline for 7 days. The baseline characteristics of patients before and after treatment and cardiac function (N-terminal pro B-type natriuretic peptide (NT-proBNP) level and left ventricular ejection fraction (LVEF) value) were analyzed. Serological analysis (sirtuin-1 (SIRT1), sirtuin-3 (SIRT3), sirtuin-6 (SIRT6), reactive oxygen species (ROS), and endothelin) was also performed. Among the 60 patients with HF who were treated with NAD + for 7 days, the","excerpt":"Based on using conventional drugs to treat HF, patients (n = 60) were randomized 1:1 to saline and 50 mg NAD + with 50 mL of normal saline for 7 days. The baseline characteristics of patients before and after treatment and cardiac function (N-terminal pro B-type natriuretic peptide (NT-proBNP) level and left ventricular ejection fraction (LVEF) value) were analyzed. Serological analysis (sirtuin-1 (SIRT1), sirtuin-3 (SIRT3), sirtuin-6 (SIRT6), reactive oxygen species (ROS), and endothelin) was also performed. Among the 60 patients with HF who were treated with NAD + for 7 days, the improvement rate in NT-proBNP levels and LVEF values was better than in the saline group, although not statistically significant. These patients were more likely to benefit from NAD + because of higher levels of anti-oxidative stress (SIRT1, SIRT3, SIRT6, and ROS) and anti-endothelial injury (endothelin) than those in the saline control group. According to the results of this study, it is believed that 7 days of NAD + injections has a positive effect on improving cardiac function, oxidative stress, and endothelial injury in patients with HF compared with the saline control. Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ ) ChiCTR2300074326; retrospectively registered on 3 August 2023. Keywords: heart failure, NAD + , clinical study, adjuvant therapy Heart failure (HF) poses a serious threat to human health and is characterized by high morbidity, high mortality, a high rehospitalization rate, and many high-risk groups. The American Heart Association/American College of Cardiology guidelines define HF as “a complex clinical syndrome caused by any structural or functional heart disease that affects the ability of the ventricles to fill and shoot blood” [ 1 ]. Benjamin et al . [ 2 ] reported that patients hospitalized for HF are at an increased risk of HF rehospitalization and cardiovascular death. One in eight deaths is due to HF, and the mortality rate within 5 years of diagnosis is as high as 50%, exceeding that of some malignancies [ 2 ]. Despite the increased number of drugs used to treat HF, the fatality rate remains high. The 2021 European Society of Cardiology guidelines recommend a combination of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin-receptor neprilysin inhibitor, β -blockers, and aldosterone receptor antagonists (MRAs) as the primary treatment for chronic HF [ 3 ]. Both the previous “golden triangle” ( β -blocker, ACEI/angiotensin II receptor blocker [ARB], and MRA) and the current “five golden flowers” ( β -blocker, ACEI/ARB, MRA, and sodium-dependent glucose transporter 2 inhibitors) have limitations in clinical treatment [ 4 , 5 , 6 ]. Current drug therapy still cannot meet the needs of HF management, making it necessary to develop new treatment ideas and explore new treatment strategies. Nicotinamide adenine dinucleotide (NAD + ) is an important cofactor and a key metabolic enzyme substrate involved in redox reactions in the mitochondria, which is greatly significant in maintaining the balance of NAD + in vivo for normal human metabolism [ 7 ]. Several studies have shown that NAD + can inhibit inflammation and oxidative stress injury in endothelial cells, reduce apoptosis in microvascular endothelial cells, promote microangiogenesis, and improve microvascular injury caused by coronary microcirculation and myocardial ischemia-reperfusion [ 8 ]. Studies have also shown that the NAD + concentration in the blood of patients with HF is significantly lower than in healthy people, and with an increase in age, NAD + also has a trend of gradually decreasing [ 7 , 9 ]. Therefore, stabilizing intracellular NAD + levels through exogenous NAD + supplementation is expected to be a therapeutic strategy for improving cardiac bioenergetics and function. HF is the leading cause of hospitalization among older populations worldwide, with a high mortality rate and impact on the quality of life of patients [ 10 , 11 ]. With the development of medical technology, various drugs have emerged to treat HF. However, the effectiveness of these drugs remains unsatisfactory. HF remains an intractable disease, with an increased burden of hospitalization and a continuous loss of health care expenditure [ 12 ]. Therefore, it is necessary to identify alternative and complementary treatment options. Thus, we sought to evaluate whether NAD + therapy has some clinical efficacy in patients with HF. NAD + is widely present in the mitochondria of myocardial tissue, and NAD + activates the deacetylation activity of sirtuins, regulates the activity of numerous aging-related transcription factors, and intervenes in aging and aging-related diseases [ 9 , 13 , 14 ]. Several studies have shown that NAD + has beneficial effects on cardiovascular diseases by regulating metabolism, maintaining redox homeostasis, and modulating immune responses [ 15 , 16 , 17 ]. Studies have found that NAD + levels are significantly reduced in patients with HF [ 18 , 19 ]. In a rat model of myocardial infarction, compared with the LCZ696-positive drug control group, using NAD + improved some cardiac function and hemodynamic indexes and could further increase the left ventricular stroke output and systolic and diastolic blood pressure [ 20 ]. In the present clinical trial, we tested whether using exogenous NAD + supplementation as a new adjuvant treatment for HF is possible. NT-proBNP and LVEF are the most widely used laboratory indices for evaluating HF severity and prognosis. In our clinical trial, NT-proBNP levels improved in both groups, possibly because patients in both groups were rigorously treated with anti-HF drugs. However, the improvement was more obvious in the NAD + group than in the saline control group, which better reflects that the therapeutic effect of NAD + in patients with HF is independent of conventional medication for HF. Although the NT-proBNP level in the NAD + group improved from baseline, no statistically significant difference was found over time. This finding may be due to the large dispersion of the data, short treatment course, and small sample size; similarly, due to short-term drug use, changes in the structure and function of the heart cannot be obvious over a short time. Moreover, the measurement of LVEF is subjective to a certain extent and is related to the experience of the tester. LVEF in the NAD + group was improved, with no statistical difference between the groups. Studies have found that women may have lower NAD + concentrations and benefit most from improved heart function [ 21 , 22 ]. In our study, there was no statistical difference in gender between the two groups of patients, and whether women can benefit more from NAD + treatment will be our major direction in the future. Oxidative stress plays an important role in HF occurrence and progression [ 23 ]. The sirtuin family is also linked to several antioxidant and oxidative stress-related processes and functions [ 24 ]. Sirtuins are a family of seven enzymes (sirtuin1–7) involved in regulating many metabolic processes [ 25 ]. Sirtuin agonists are more convincing than existing deacetylase inhibitors for the treatment of cardiovascular diseases in terms of safety and efficacy and may have clinical value for treating multiple types of cardiovascular diseases [ 26 ]. Increasing the NAD + level in vivo can activate sirtuins, which can significantly inhibit myocardial hyperacetylation and improve myocardial mitochondrial function [ 27 ]. Clemency et al . [ 28 ] found that sodium-glucose cotransporter 2 (SGL-2) inhibitor could inhibit oxidative stress by increasing the expression of SIRT1 and SIRT3 and decreasing the expression of SIRT6, thereby alleviating myocardial injury. In our clinical trial, the SIRT1, SIRT3, and SIRT6 levels increased at the 2-week follow-up after medication, but over time, the concentration of exogenous supplemental NAD + gradually decreased in vivo and showed a trend of gradual decrease in the last two follow-up visits, which is also consistent with the metabolic process of intravenous drug use in the body. Furthermore, there was an interaction between SIRT1 in the saline control group and the NAD + group, which confirmed that NAD + plays a critical role in anti-oxidative stress. We observed that ROS levels increased in the NAD + group at the 2-week follow-up visit, possibly due to the negative feedback reaction of inflammation caused by the strong antioxidant effect in the short term. However, those levels improved at later visits. Increased levels of ET, the most potent vasoconstrictor, are produced by the pro-peptide precursor, large ET, through ET convertase [ 29 ]. ET in the peripheral blood of patients with HF can predict poor prognosis [ 30 , 31 , 32 ]. In this clinical trial, there were significant differences in ET levels between the saline control and NAD + groups, which confirmed that NAD + plays a more critical role in anti-endothelial injury. Although there was no difference in the incidence of composite endpoint events (including all-cause death and readmission due to HF) during the 1-year follow-up period in this study, there was still a significant difference in mortality between the two groups. The survival rate of NAD + was higher, and most patients who died were in the saline control group, usually 2–4 months after treatment. These results suggest that the use of NAD + may delay the progression of HF and reduce short-term mortality. The reason why no statistical difference was found in the various clinical endpoints in this study may be related to the small number of study cases, the short duration of NAD + administration, and the short follow-up time. Nevertheless, this study has expanded our ideas for exploring new treatments for patients with HF and confirmed their therapeutic effect on patients with HF based on molecular biology and echocardiography evaluation indicators. We also expect this study’s results to guide follow-up national multicenter, large-sample, prospective, randomized, double-blind controlled studies. We further confirmed the therapeutic effects of NAD + in the HF population. According to the product instructions, NAD + occasionally has side effects such as dry mouth, nausea, dizziness, and palpitations. However, in this clinical trial, patients had no obvious complaints after 7 days of intravenously administering NAD + , but the long-term effect or safety of treatment still needs to be observed over a longer study period. In addition, the follow-up of participants after completing this clinical trial may be limited, making it difficult to assess long-term outcomes and treatment safety. Our study consisted of a small sample size from a single center, potentially limiting the generalizability of our findings to a broader population of HF patients. Future multicenter studies covering cohorts with different demographic and clinical characteristics would help validate our findings and enhance external validity. In addition, we did not perform cardiovascular magnetic resonance to assess patients with HF more comprehensively. We did not discuss the pharmacological background of HF patients further, and our future research direction will be to focus on their pharmacological background. Among patients with HF, those injected with NAD + for 7 days may benefit more from improved cardiac function, levels of anti-oxidative stress, and endothelial injury than those re"},{"source_id":"source_12","study":"Oral MIB‐626 (β Nicotinamide Mononucleotide) Safely Raises Blood Nicotinamide Adenine Dinucleotide Levels in Hospitalized Patients With COVID‐19 and Acute Kidney Injury: A Randomized Controlled Trial","doi":"10.1096/fba.2025-00014","url":"https://doi.org/10.1096/fba.2025-00014","support_kind":"bundle_reference","cited_as":"Pencina 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"To determine whether MIB‐626 ( β‐ nicotinamide mononucleotide), an NAD + precursor, can safely increase blood NAD + levels and attenuate acute kidney injury (AKI) and inflammation in hospitalized patients with COVID‐19, 42 adults, ≥ 18 years, hospitalized with COVID‐19 and AKI, were randomized in a 3:2 ratio to MIB‐626 1.0‐g or placebo tablets twice daily for 14 days. Circulating NAD + and its metabolites, markers of AKI, inflammation, and disease severity, were assessed. MIB‐626 treatment significantly but gradually raised blood NAD + levels to a peak between 5 to 14 days (16.0 ± 6.9, 25.5 ±","excerpt":"To determine whether MIB‐626 ( β‐ nicotinamide mononucleotide), an NAD + precursor, can safely increase blood NAD + levels and attenuate acute kidney injury (AKI) and inflammation in hospitalized patients with COVID‐19, 42 adults, ≥ 18 years, hospitalized with COVID‐19 and AKI, were randomized in a 3:2 ratio to MIB‐626 1.0‐g or placebo tablets twice daily for 14 days. Circulating NAD + and its metabolites, markers of AKI, inflammation, and disease severity, were assessed. MIB‐626 treatment significantly but gradually raised blood NAD + levels to a peak between 5 to 14 days (16.0 ± 6.9, 25.5 ± 12.6, and 42.6 ± 25.6 μg/mL at baseline, days 5 and 14) and raised plasma concentrations of NAD + metabolites 1‐methylnicotinamide, N‐methyl, 2‐pyridone, 4‐carboxamide rapidly to a peak by day 3. Changes in serum creatinine, cystatin‐C, and serum markers of AKI did not differ significantly between groups. Serum CRP, IL‐6, and TNFα and indices of disease severity also did not differ between groups. MIB‐626 treatment of patients with COVID‐19 and AKI safely and substantially raised blood NAD + and plasma concentrations of NAD + metabolites. Markers of AKI, inflammation, and disease severity did not differ between groups, likely due to the slow rise in NAD + levels. Future studies should assess whether a rapid increase in NAD + by parenteral administration can attenuate disease severity and AKI. Trial Registration: ClinicalTrials.gov Identifier: NCT05038488 Keywords: acute kidney injury, COVID‐19, NAD augmentation, NAD metabolism, NAD precursor, nicotinamide mononucleotide This placebo‐controlled, randomized, parallel group, double‐blind trial was conducted at 3 trial sites: Brigham and Women's Hospital in Boston, MA; University of Texas Medical Branch, Galveston, TX; and Tulane University Medical Center, New Orleans, LA. The study protocol was approved by the trial's single institutional review board (sIRB) at the Mass General Brigham Human Research Protection Program and the institutional review boards of the participating trial sites ceded to the sIRB. An independent Data and Safety Monitoring Board (DSMB) reviewed the safety data and study progress every 6 weeks to 3 months. The participants provided consent and authorization for the use and disclosure of personal health information in accordance with the Health Insurance Portability and Accountability Act. The trial was registered at ClinicalTrials.gov . This is the first randomized, placebo‐controlled trial of NAD + augmentation in patients hospitalized with moderately severe SARS‐CoV‐2 infection to show that MIB‐626 was safe, well tolerated, and efficacious in raising blood NAD + levels in patients with COVID‐19. The present study also shows that blood NAD + levels are only modestly lower in patients with COVID‐19 compared to healthy adults without COVID‐19 but that the circulating concentrations of NAD + metabolites such as MeNAM, NAM, and 2‐PY are markedly increased in patients with COVID‐19 compared with healthy adults, suggesting increased turnover of NAD + due to marked upregulation of enzymes involved in NAD consumption as well as synthesis, as suggested by our previous observational study of patients with COVID‐19 [ 16 ]. In spite of the increased NAD + turnover during acute COVID‐19, the MIB‐626 regimen used in this study (1.0 g twice daily) significantly raised NAD + levels, although the increment above baseline was lower than that observed in our previous studies in healthy adults with a similar dose regimen [ 18 , 19 ]. Consistent with our previous phase 1 studies [ 18 , 19 ], blood NAD + levels rose gradually in MIB‐626‐treated patients and reached the peak steady state levels between days 5 and 14, even though the plasma levels of its metabolites, MeNAM and 2‐PY, reached peak levels by day 3, which was the earliest sampling time point after randomization. The reasons for the slow ramp up of blood NAD + levels in spite of a more rapid increase in circulating levels of its metabolites after oral NMN administration are not clear. It is possible that a longer time period is required to reach peak steady state levels due to the substantially increased NAD + turnover in patients with COVID‐19. The mechanisms by which oral NAD + precursors, NMN and NR, increase blood and tissue NAD + levels need further investigation by metabolic flux studies using stable isotope‐labeled NAD + precursors. This relatively small trial did not reveal significant differences in serum creatinine or cystatin C or other serum markers of acute kidney injury, or in other clinical indices of disease severity. Due to the small sample size and substantial variability in the study's clinical endpoints in acutely ill patients with multiple comorbidities, the study likely did not have sufficient statistical power to detect meaningful differences in these endpoints. It took more than 5 days to achieve peak NAD + levels by which time, many patients had been discharged and this may have obscured the drug's efficacy."},{"source_id":"source_15","study":"An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers","doi":"10.1371/journal.pone.0186459","url":"https://doi.org/10.1371/journal.pone.0186459","support_kind":"bundle_reference","cited_as":"Airhart 2017","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","quote":"Significant increases comparing baseline to mean concentrations at steady state (C ave,ss ) were observed for both NR ( p = 0.03) and NAD+ ( p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R 2 = 0.72, p = 0.008).","evidence_span":"Significant increases comparing baseline to mean concentrations at steady state (C ave,ss ) were observed for both NR ( p = 0.03) and NAD+ ( p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R 2 = 0.72, p = 0.008).","excerpt":"Significant increases comparing baseline to mean concentrations at steady state (C ave,ss ) were observed for both NR ( p = 0.03) and NAD+ ( p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R 2 = 0.72, p = 0.008). Because NR increases circulating NAD+ in humans, NR may have potential as a therapy in patients with mitochondrial dysfunction due to genetic and/or acquired diseases. Mitochondrial dysfunction has been implicated in multiple diseases, including heart failure [ 1 – 3 ]. However, there currently is no specific treatment for mitochondrial dysfunction in human heart failure or any other disease [ 4 – 7 ]. In recent years, there has been a surge of interest in targeting alterations in energy metabolism in heart failure. Development of mitochondria-based therapies for metabolic diseases has been hampered both by limited understanding of how mitochondrial impairment causes tissue dysfunction as well as by a lack of interventions shown to improve mitochondrial function. Recently, we demonstrated in a murine model that impaired mitochondrial oxidative phosphorylation led to an increased myocardial NADH/NAD+ ratio and increased mitochondrial protein acetylation without affecting mitochondrial production of reactive oxygen species (ROS) or synthesis of adenosine triphosphate (ATP) [ 8 ]. These changes rendered the heart susceptible to chronic stresses, which accelerated the development of heart failure. Similar increases in the NADH/NAD+ ratio and in protein acetylation also were seen in animal models of heart failure due to chronic pressure overload. Furthermore, intraperitoneal administration of the NAD+ precursor nicotinamide mononucleotide (NMN) to these mice normalized the NADH/NAD+ ratio, prevented the increase in mitochondrial protein acetylation, and improved cardiac function [ 9 ]. Promoting NAD+ synthesis through the salvage pathway by overexpressing nicotinamide phosphoribotransferase protected against ischemia-reperfusion injury and ischemic heart failure [ 10 , 11 ]. These findings collectively suggest that augmentation of NAD+ could improve mitochondrial function and exert myocardial protection. Nicotinamide riboside (NR) is a pyridine nucleoside form of vitamin B3 that is naturally found in milk and is available as a nutraceutical. NR is converted by nicotinamide riboside kinases (NRK1,2) to NMN, which is subsequently converted to NAD+ by nicotinamide mononucleotide adenylyltransferase (NMNAT). Oral supplementation with NR has been shown to increase NAD+ in brown adipose tissue, skeletal muscle and liver, and to improve mitochondrial function in a mouse model of diet-induced obesity [ 12 ]. Nutritional supplementation with NR, an NAD+ precursor, thus holds potential as an innovative therapy for heart failure and other disease states characterized by mitochondrial dysfunction. However, very limited information is available in regard to whether NR supplementation augments NAD+ levels in humans. Therefore, the primary objective of this study was to determine the pharmacokinetics of orally administered NR and its ability to increase blood NAD+ in healthy subjects following dose escalation of NR to 1000 mg twice daily. Primary outcomes were comparisons of baseline concentrations versus mean concentrations at steady state (C ave,ss ) on Day 9 for NR and NAD+. Secondary outcomes were to determine the safety and tolerability of NR by assessing adverse event rates and comparisons of laboratory tests, specifically serum levels of potassium, creatine kinase (myositis), glucose (insulin resistance), uric acid and alanine aminotransferase. During assay development before starting the study, NR was found to be highly unstable in blood, although the combination of 2.5 M citric acid and ACD solution improved NR stability in blood. At room temperature, the absolute peak heights of NR and the deuterated internal standard spiked into blood and processed as described in the methods section decreased by 8% to 14% over 30 min, but their ratios remained constant. While the latter observation means quantitation relying on signal ratio between analyte and internal standard is feasible in the event of ex vivo degradation or consumption, the decrease in absolute signal does limit our assay sensitivity (i.e., LLOQ). At the temperature of wet ice, spiked NR and deuterated internal standard appeared stable for 20 min, but decreased by 22% in 1 hour. This led to our current practice of processing the blood samples immediately to limit the lapse between blood draw and stabilization to < 5 min. NR in the sample becomes stable once blood proteins are precipitated, which allowed us to process the samples on the LC-MS/MS over the required run time. Also, storage data thus far indicate that NR blood samples are stable at –80°C for at least 3 weeks. With the resolution of NR’s instability problem, we were able to generate for the first time pharmacokinetic data on NR in human subjects. It should also be noted that we did try to measure NR in the plasma fraction of a few blood samples obtained from volunteers following ingestion of NR, but failed to detect measurable levels of the riboside. We concluded that NR is concentrated in the cellular fraction of blood. Because NR’s instability in blood ex vivo, we decided to avoid the delay in separating cells from blood samples, and instead assay whole blood concentration. Similar to NR, NAD+ is unstable in blood samples at room temperature. Measured levels of NAD+ spiked into thawed, room-temperature whole blood degraded by as much as 50% in 10 minutes. NAD+ degraded at a much slower rate (~3–4% decrease in 10 minutes) when blood samples were placed on wet ice. Also, NAD+ is stable in blood when stored at –80°C for at least 3 weeks. Hence, blood samples collected for NAD+ analysis were immediately placed on wet ice and then frozen in dry ice within 5 minutes of collection. Once blood proteins were precipitated with TCA, NAD+ in the supernatant remained stable for at least 48 hours while the samples were being processed on the LC-MS. Also, instability, at least over a few hours, was not observed when NAD+ was spiked into BSA rather than blood, suggesting that the disappearance of signal is not due to chemical instability. This pilot study yielded several important findings. First, successful and reliable methods for collection, processing and measurement of NR and NAD+ in human blood were developed, overcoming the severe instability problems that have prevented previous investigations into the clinical pharmacokinetics of NR in blood or tissue. These methods allowed us to determine the pharmacokinetic profile of orally administered NR in healthy human volunteers. Second, the study demonstrated that an NR dose of 1000 mg twice daily significantly increased steady-state, whole-blood levels of NAD+ in all study participants with individual increases ranging from 35–168% above baseline NAD+ levels. Finally, the study demonstrated that measurable, biologic effects on NAD+ levels can be achieved in healthy volunteers at NR doses that are well-tolerated. Specifically, participants reported none of the serious side effects seen with similar doses of niacin, such as flushing, pruritus, hyperglycemia, hyperuricemia, or elevations in liver or muscle enzymes [ 17 , 18 ]. Together, these findings support the feasibility of studying NR as a potential therapy for diseases in which mitochondrial dysfunction has been implicated. At the time of our manuscript submission, Trammell et al. [ 16 ] reported a similar study on NAD+ metabolome in peripheral blood mononuclear cells (PBMC) in twelve healthy human subjects after single oral ingestion of NR at three different dose levels: 30, 100 and 1000 mg. Their findings are consistent with our experience and observations after 9 consecutive days of NR treatment at a final daily dose of 1000 mg. Over the 36 days of observation, Trammell et al. did not observe any serious adverse event and any event that was dose-related. Mean PBMC NAD+ concentration at 24-hours for pooled data across all three dose levels was significantly elevated compared to pre-dose concentration (p ≤ 0.03)."},{"source_id":"source_16","study":"Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD + in healthy middle-aged and older adults","doi":"10.1038/s41467-018-03421-7","url":"https://doi.org/10.1038/s41467-018-03421-7","support_kind":"bundle_reference","cited_as":"Martens 2018","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"A follow-up analysis suggested that this trend was most pronounced in individuals with baseline BP between 120 and 139 mmHg, a subgroup currently classified clinically as having either “elevated” SBP (120–129 mmHg) or stage 1 systolic hypertension (130–139 mmHg). The mean decrease in SBP after NR treatment in this subgroup approached 10 mmHg—a magnitude of change associated with a 25% decrease in incident CV events in a recent major anti-hypertensive drug trial in older adults 44 . If this magnitude of SBP reduction with NR supplementation is confirmed in a larger clinical trial, such an","excerpt":"A follow-up analysis suggested that this trend was most pronounced in individuals with baseline BP between 120 and 139 mmHg, a subgroup currently classified clinically as having either “elevated” SBP (120–129 mmHg) or stage 1 systolic hypertension (130–139 mmHg). The mean decrease in SBP after NR treatment in this subgroup approached 10 mmHg—a magnitude of change associated with a 25% decrease in incident CV events in a recent major anti-hypertensive drug trial in older adults 44 . If this magnitude of SBP reduction with NR supplementation is confirmed in a larger clinical trial, such an effect could have broad biomedical implications. SBP in this range (120−139 mmHg) is observed in ~50% of all middle-aged and older adults in the U.S. 45 Moreover, SBP < 140 mmHg is responsible for at least one-third of all BP-attributable deaths 46 and is associated with increased risk of heart disease, stroke, cognitive impair"}],"candidate_sources":[]},{"claim_id":"claim_8","claim":"The current evidence base presents significant cross-outcome tensions that must be explicitly addressed. For instance, while one trial reported a trend toward improved NYHA class in heart failure patients [Yu 2025] [bundle:4], other trials in different populations found null effects on functional endpoints, such as mitochondrial respiration and skeletal muscle function in older adults [Connell 2021] [bundle:5] and cognition in long-COVID patients [Wu 2025] [bundle:1] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.1093/jn/nxab193] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633]. This synthesis will separate mechanistic evidence from clinical evidence, acknowledging that biochemical changes (for example, increased NAD+ levels) do not automatically confer clinical benefit. The structured evidence weighting will prioritize direct human RCT data with cardiovascular endpoints, while clearly delineating the indirect evidence from trials focused on other outcomes. The goal is to provide a transparent assessment of where the evidence is strong, where it is suggestive, and where significant gaps remain, particularly regarding the long-term cardiovascular effects of NAD+ precursor supplementation in diverse human populations.","citation_support":[{"source_id":"source_1","study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","support_kind":"bundle_reference","cited_as":"Wu 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig."},{"source_id":"source_4","study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","support_kind":"bundle_reference","cited_as":"Yu 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115)."},{"source_id":"source_5","study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","support_kind":"bundle_reference","cited_as":"Connell 2021","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR"}],"candidate_sources":[]},{"claim_id":"claim_9","claim":"The evidence profile indicates that the case for NAD+ precursors as cardiovascular therapeutics is currently incomplete. Mechanistic plausibility is supported by the central role of NAD+ in cellular metabolism and the consistent ability of oral precursors to raise circulating levels [Airhart 2017 [bundle:15], Xue 2022 [bundle:7]] [exact source: https://doi.org/10.1371/journal.pone.0186459] [exact source: https://doi.org/10.3390/nu14112219]. However, the human RCT evidence is sparse and mixed. Direct cardiovascular trials are limited to small studies in heart failure populations with short follow-up and non-significant or trend-level between-group differences [Yu 2025 [bundle:4], Pei 2024 [bundle:11]] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.31083/j.rcm2508297]. The broader trial landscape includes studies in non-cardiovascular populations where cardiovascular endpoints were not assessed or were secondary [Wu 2025 [bundle:1], Gao 2025 [bundle:2], Roy 2026 [bundle:9]] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633] [exact source: https://doi.org/10.1002/lary.70173] [exact source: https://doi.org/10.1002/trc2.70278]. Furthermore, some trials in relevant populations, such as older adults, have failed to show functional benefits on muscle or mitochondrial endpoints [Connell 2021] [bundle:5] [exact source: https://doi.org/10.1093/jn/nxab193]. The boundary conditions for any potential benefit—including optimal dose, duration, patient selection, and the specific cardiovascular outcomes that might respond—remain to be established. This synthesis aims to map these boundaries by systematically evaluating the available evidence, highlighting both the promises and the significant uncertainties that currently define the field.","citation_support":[{"source_id":"source_1","study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","support_kind":"bundle_reference","cited_as":"Wu 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig."},{"source_id":"source_4","study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","support_kind":"bundle_reference","cited_as":"Yu 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115)."},{"source_id":"source_5","study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","support_kind":"bundle_reference","cited_as":"Connell 2021","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR"},{"source_id":"source_11","study":"Effects of Nicotinamide Adenine Dinucleotide on Older Patients with Heart Failure","doi":"10.31083/j.rcm2508297","url":"https://doi.org/10.31083/j.rcm2508297","support_kind":"bundle_reference","cited_as":"Pei 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"Based on using conventional drugs to treat HF, patients (n = 60) were randomized 1:1 to saline and 50 mg NAD + with 50 mL of normal saline for 7 days. The baseline characteristics of patients before and after treatment and cardiac function (N-terminal pro B-type natriuretic peptide (NT-proBNP) level and left ventricular ejection fraction (LVEF) value) were analyzed. Serological analysis (sirtuin-1 (SIRT1), sirtuin-3 (SIRT3), sirtuin-6 (SIRT6), reactive oxygen species (ROS), and endothelin) was also performed. Among the 60 patients with HF who were treated with NAD + for 7 days, the","excerpt":"Based on using conventional drugs to treat HF, patients (n = 60) were randomized 1:1 to saline and 50 mg NAD + with 50 mL of normal saline for 7 days. The baseline characteristics of patients before and after treatment and cardiac function (N-terminal pro B-type natriuretic peptide (NT-proBNP) level and left ventricular ejection fraction (LVEF) value) were analyzed. Serological analysis (sirtuin-1 (SIRT1), sirtuin-3 (SIRT3), sirtuin-6 (SIRT6), reactive oxygen species (ROS), and endothelin) was also performed. Among the 60 patients with HF who were treated with NAD + for 7 days, the improvement rate in NT-proBNP levels and LVEF values was better than in the saline group, although not statistically significant. These patients were more likely to benefit from NAD + because of higher levels of anti-oxidative stress (SIRT1, SIRT3, SIRT6, and ROS) and anti-endothelial injury (endothelin) than those in the saline control group. According to the results of this study, it is believed that 7 days of NAD + injections has a positive effect on improving cardiac function, oxidative stress, and endothelial injury in patients with HF compared with the saline control. Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ ) ChiCTR2300074326; retrospectively registered on 3 August 2023. Keywords: heart failure, NAD + , clinical study, adjuvant therapy Heart failure (HF) poses a serious threat to human health and is characterized by high morbidity, high mortality, a high rehospitalization rate, and many high-risk groups. The American Heart Association/American College of Cardiology guidelines define HF as “a complex clinical syndrome caused by any structural or functional heart disease that affects the ability of the ventricles to fill and shoot blood” [ 1 ]. Benjamin et al . [ 2 ] reported that patients hospitalized for HF are at an increased risk of HF rehospitalization and cardiovascular death. One in eight deaths is due to HF, and the mortality rate within 5 years of diagnosis is as high as 50%, exceeding that of some malignancies [ 2 ]. Despite the increased number of drugs used to treat HF, the fatality rate remains high. The 2021 European Society of Cardiology guidelines recommend a combination of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin-receptor neprilysin inhibitor, β -blockers, and aldosterone receptor antagonists (MRAs) as the primary treatment for chronic HF [ 3 ]. Both the previous “golden triangle” ( β -blocker, ACEI/angiotensin II receptor blocker [ARB], and MRA) and the current “five golden flowers” ( β -blocker, ACEI/ARB, MRA, and sodium-dependent glucose transporter 2 inhibitors) have limitations in clinical treatment [ 4 , 5 , 6 ]. Current drug therapy still cannot meet the needs of HF management, making it necessary to develop new treatment ideas and explore new treatment strategies. Nicotinamide adenine dinucleotide (NAD + ) is an important cofactor and a key metabolic enzyme substrate involved in redox reactions in the mitochondria, which is greatly significant in maintaining the balance of NAD + in vivo for normal human metabolism [ 7 ]. Several studies have shown that NAD + can inhibit inflammation and oxidative stress injury in endothelial cells, reduce apoptosis in microvascular endothelial cells, promote microangiogenesis, and improve microvascular injury caused by coronary microcirculation and myocardial ischemia-reperfusion [ 8 ]. Studies have also shown that the NAD + concentration in the blood of patients with HF is significantly lower than in healthy people, and with an increase in age, NAD + also has a trend of gradually decreasing [ 7 , 9 ]. Therefore, stabilizing intracellular NAD + levels through exogenous NAD + supplementation is expected to be a therapeutic strategy for improving cardiac bioenergetics and function. HF is the leading cause of hospitalization among older populations worldwide, with a high mortality rate and impact on the quality of life of patients [ 10 , 11 ]. With the development of medical technology, various drugs have emerged to treat HF. However, the effectiveness of these drugs remains unsatisfactory. HF remains an intractable disease, with an increased burden of hospitalization and a continuous loss of health care expenditure [ 12 ]. Therefore, it is necessary to identify alternative and complementary treatment options. Thus, we sought to evaluate whether NAD + therapy has some clinical efficacy in patients with HF. NAD + is widely present in the mitochondria of myocardial tissue, and NAD + activates the deacetylation activity of sirtuins, regulates the activity of numerous aging-related transcription factors, and intervenes in aging and aging-related diseases [ 9 , 13 , 14 ]. Several studies have shown that NAD + has beneficial effects on cardiovascular diseases by regulating metabolism, maintaining redox homeostasis, and modulating immune responses [ 15 , 16 , 17 ]. Studies have found that NAD + levels are significantly reduced in patients with HF [ 18 , 19 ]. In a rat model of myocardial infarction, compared with the LCZ696-positive drug control group, using NAD + improved some cardiac function and hemodynamic indexes and could further increase the left ventricular stroke output and systolic and diastolic blood pressure [ 20 ]. In the present clinical trial, we tested whether using exogenous NAD + supplementation as a new adjuvant treatment for HF is possible. NT-proBNP and LVEF are the most widely used laboratory indices for evaluating HF severity and prognosis. In our clinical trial, NT-proBNP levels improved in both groups, possibly because patients in both groups were rigorously treated with anti-HF drugs. However, the improvement was more obvious in the NAD + group than in the saline control group, which better reflects that the therapeutic effect of NAD + in patients with HF is independent of conventional medication for HF. Although the NT-proBNP level in the NAD + group improved from baseline, no statistically significant difference was found over time. This finding may be due to the large dispersion of the data, short treatment course, and small sample size; similarly, due to short-term drug use, changes in the structure and function of the heart cannot be obvious over a short time. Moreover, the measurement of LVEF is subjective to a certain extent and is related to the experience of the tester. LVEF in the NAD + group was improved, with no statistical difference between the groups. Studies have found that women may have lower NAD + concentrations and benefit most from improved heart function [ 21 , 22 ]. In our study, there was no statistical difference in gender between the two groups of patients, and whether women can benefit more from NAD + treatment will be our major direction in the future. Oxidative stress plays an important role in HF occurrence and progression [ 23 ]. The sirtuin family is also linked to several antioxidant and oxidative stress-related processes and functions [ 24 ]. Sirtuins are a family of seven enzymes (sirtuin1–7) involved in regulating many metabolic processes [ 25 ]. Sirtuin agonists are more convincing than existing deacetylase inhibitors for the treatment of cardiovascular diseases in terms of safety and efficacy and may have clinical value for treating multiple types of cardiovascular diseases [ 26 ]. Increasing the NAD + level in vivo can activate sirtuins, which can significantly inhibit myocardial hyperacetylation and improve myocardial mitochondrial function [ 27 ]. Clemency et al . [ 28 ] found that sodium-glucose cotransporter 2 (SGL-2) inhibitor could inhibit oxidative stress by increasing the expression of SIRT1 and SIRT3 and decreasing the expression of SIRT6, thereby alleviating myocardial injury. In our clinical trial, the SIRT1, SIRT3, and SIRT6 levels increased at the 2-week follow-up after medication, but over time, the concentration of exogenous supplemental NAD + gradually decreased in vivo and showed a trend of gradual decrease in the last two follow-up visits, which is also consistent with the metabolic process of intravenous drug use in the body. Furthermore, there was an interaction between SIRT1 in the saline control group and the NAD + group, which confirmed that NAD + plays a critical role in anti-oxidative stress. We observed that ROS levels increased in the NAD + group at the 2-week follow-up visit, possibly due to the negative feedback reaction of inflammation caused by the strong antioxidant effect in the short term. However, those levels improved at later visits. Increased levels of ET, the most potent vasoconstrictor, are produced by the pro-peptide precursor, large ET, through ET convertase [ 29 ]. ET in the peripheral blood of patients with HF can predict poor prognosis [ 30 , 31 , 32 ]. In this clinical trial, there were significant differences in ET levels between the saline control and NAD + groups, which confirmed that NAD + plays a more critical role in anti-endothelial injury. Although there was no difference in the incidence of composite endpoint events (including all-cause death and readmission due to HF) during the 1-year follow-up period in this study, there was still a significant difference in mortality between the two groups. The survival rate of NAD + was higher, and most patients who died were in the saline control group, usually 2–4 months after treatment. These results suggest that the use of NAD + may delay the progression of HF and reduce short-term mortality. The reason why no statistical difference was found in the various clinical endpoints in this study may be related to the small number of study cases, the short duration of NAD + administration, and the short follow-up time. Nevertheless, this study has expanded our ideas for exploring new treatments for patients with HF and confirmed their therapeutic effect on patients with HF based on molecular biology and echocardiography evaluation indicators. We also expect this study’s results to guide follow-up national multicenter, large-sample, prospective, randomized, double-blind controlled studies. We further confirmed the therapeutic effects of NAD + in the HF population. According to the product instructions, NAD + occasionally has side effects such as dry mouth, nausea, dizziness, and palpitations. However, in this clinical trial, patients had no obvious complaints after 7 days of intravenously administering NAD + , but the long-term effect or safety of treatment still needs to be observed over a longer study period. In addition, the follow-up of participants after completing this clinical trial may be limited, making it difficult to assess long-term outcomes and treatment safety. Our study consisted of a small sample size from a single center, potentially limiting the generalizability of our findings to a broader population of HF patients. Future multicenter studies covering cohorts with different demographic and clinical characteristics would help validate our findings and enhance external validity. In addition, we did not perform cardiovascular magnetic resonance to assess patients with HF more comprehensively. We did not discuss the pharmacological background of HF patients further, and our future research direction will be to focus on their pharmacological background. Among patients with HF, those injected with NAD + for 7 days may benefit more from improved cardiac function, levels of anti-oxidative stress, and endothelial injury than those re"},{"source_id":"source_15","study":"An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers","doi":"10.1371/journal.pone.0186459","url":"https://doi.org/10.1371/journal.pone.0186459","support_kind":"bundle_reference","cited_as":"Airhart 2017","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","quote":"Significant increases comparing baseline to mean concentrations at steady state (C ave,ss ) were observed for both NR ( p = 0.03) and NAD+ ( p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R 2 = 0.72, p = 0.008).","evidence_span":"Significant increases comparing baseline to mean concentrations at steady state (C ave,ss ) were observed for both NR ( p = 0.03) and NAD+ ( p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R 2 = 0.72, p = 0.008).","excerpt":"Significant increases comparing baseline to mean concentrations at steady state (C ave,ss ) were observed for both NR ( p = 0.03) and NAD+ ( p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R 2 = 0.72, p = 0.008). Because NR increases circulating NAD+ in humans, NR may have potential as a therapy in patients with mitochondrial dysfunction due to genetic and/or acquired diseases. Mitochondrial dysfunction has been implicated in multiple diseases, including heart failure [ 1 – 3 ]. However, there currently is no specific treatment for mitochondrial dysfunction in human heart failure or any other disease [ 4 – 7 ]. In recent years, there has been a surge of interest in targeting alterations in energy metabolism in heart failure. Development of mitochondria-based therapies for metabolic diseases has been hampered both by limited understanding of how mitochondrial impairment causes tissue dysfunction as well as by a lack of interventions shown to improve mitochondrial function. Recently, we demonstrated in a murine model that impaired mitochondrial oxidative phosphorylation led to an increased myocardial NADH/NAD+ ratio and increased mitochondrial protein acetylation without affecting mitochondrial production of reactive oxygen species (ROS) or synthesis of adenosine triphosphate (ATP) [ 8 ]. These changes rendered the heart susceptible to chronic stresses, which accelerated the development of heart failure. Similar increases in the NADH/NAD+ ratio and in protein acetylation also were seen in animal models of heart failure due to chronic pressure overload. Furthermore, intraperitoneal administration of the NAD+ precursor nicotinamide mononucleotide (NMN) to these mice normalized the NADH/NAD+ ratio, prevented the increase in mitochondrial protein acetylation, and improved cardiac function [ 9 ]. Promoting NAD+ synthesis through the salvage pathway by overexpressing nicotinamide phosphoribotransferase protected against ischemia-reperfusion injury and ischemic heart failure [ 10 , 11 ]. These findings collectively suggest that augmentation of NAD+ could improve mitochondrial function and exert myocardial protection. Nicotinamide riboside (NR) is a pyridine nucleoside form of vitamin B3 that is naturally found in milk and is available as a nutraceutical. NR is converted by nicotinamide riboside kinases (NRK1,2) to NMN, which is subsequently converted to NAD+ by nicotinamide mononucleotide adenylyltransferase (NMNAT). Oral supplementation with NR has been shown to increase NAD+ in brown adipose tissue, skeletal muscle and liver, and to improve mitochondrial function in a mouse model of diet-induced obesity [ 12 ]. Nutritional supplementation with NR, an NAD+ precursor, thus holds potential as an innovative therapy for heart failure and other disease states characterized by mitochondrial dysfunction. However, very limited information is available in regard to whether NR supplementation augments NAD+ levels in humans. Therefore, the primary objective of this study was to determine the pharmacokinetics of orally administered NR and its ability to increase blood NAD+ in healthy subjects following dose escalation of NR to 1000 mg twice daily. Primary outcomes were comparisons of baseline concentrations versus mean concentrations at steady state (C ave,ss ) on Day 9 for NR and NAD+. Secondary outcomes were to determine the safety and tolerability of NR by assessing adverse event rates and comparisons of laboratory tests, specifically serum levels of potassium, creatine kinase (myositis), glucose (insulin resistance), uric acid and alanine aminotransferase. During assay development before starting the study, NR was found to be highly unstable in blood, although the combination of 2.5 M citric acid and ACD solution improved NR stability in blood. At room temperature, the absolute peak heights of NR and the deuterated internal standard spiked into blood and processed as described in the methods section decreased by 8% to 14% over 30 min, but their ratios remained constant. While the latter observation means quantitation relying on signal ratio between analyte and internal standard is feasible in the event of ex vivo degradation or consumption, the decrease in absolute signal does limit our assay sensitivity (i.e., LLOQ). At the temperature of wet ice, spiked NR and deuterated internal standard appeared stable for 20 min, but decreased by 22% in 1 hour. This led to our current practice of processing the blood samples immediately to limit the lapse between blood draw and stabilization to < 5 min. NR in the sample becomes stable once blood proteins are precipitated, which allowed us to process the samples on the LC-MS/MS over the required run time. Also, storage data thus far indicate that NR blood samples are stable at –80°C for at least 3 weeks. With the resolution of NR’s instability problem, we were able to generate for the first time pharmacokinetic data on NR in human subjects. It should also be noted that we did try to measure NR in the plasma fraction of a few blood samples obtained from volunteers following ingestion of NR, but failed to detect measurable levels of the riboside. We concluded that NR is concentrated in the cellular fraction of blood. Because NR’s instability in blood ex vivo, we decided to avoid the delay in separating cells from blood samples, and instead assay whole blood concentration. Similar to NR, NAD+ is unstable in blood samples at room temperature. Measured levels of NAD+ spiked into thawed, room-temperature whole blood degraded by as much as 50% in 10 minutes. NAD+ degraded at a much slower rate (~3–4% decrease in 10 minutes) when blood samples were placed on wet ice. Also, NAD+ is stable in blood when stored at –80°C for at least 3 weeks. Hence, blood samples collected for NAD+ analysis were immediately placed on wet ice and then frozen in dry ice within 5 minutes of collection. Once blood proteins were precipitated with TCA, NAD+ in the supernatant remained stable for at least 48 hours while the samples were being processed on the LC-MS. Also, instability, at least over a few hours, was not observed when NAD+ was spiked into BSA rather than blood, suggesting that the disappearance of signal is not due to chemical instability. This pilot study yielded several important findings. First, successful and reliable methods for collection, processing and measurement of NR and NAD+ in human blood were developed, overcoming the severe instability problems that have prevented previous investigations into the clinical pharmacokinetics of NR in blood or tissue. These methods allowed us to determine the pharmacokinetic profile of orally administered NR in healthy human volunteers. Second, the study demonstrated that an NR dose of 1000 mg twice daily significantly increased steady-state, whole-blood levels of NAD+ in all study participants with individual increases ranging from 35–168% above baseline NAD+ levels. Finally, the study demonstrated that measurable, biologic effects on NAD+ levels can be achieved in healthy volunteers at NR doses that are well-tolerated. Specifically, participants reported none of the serious side effects seen with similar doses of niacin, such as flushing, pruritus, hyperglycemia, hyperuricemia, or elevations in liver or muscle enzymes [ 17 , 18 ]. Together, these findings support the feasibility of studying NR as a potential therapy for diseases in which mitochondrial dysfunction has been implicated. At the time of our manuscript submission, Trammell et al. [ 16 ] reported a similar study on NAD+ metabolome in peripheral blood mononuclear cells (PBMC) in twelve healthy human subjects after single oral ingestion of NR at three different dose levels: 30, 100 and 1000 mg. Their findings are consistent with our experience and observations after 9 consecutive days of NR treatment at a final daily dose of 1000 mg. Over the 36 days of observation, Trammell et al. did not observe any serious adverse event and any event that was dose-related. Mean PBMC NAD+ concentration at 24-hours for pooled data across all three dose levels was significantly elevated compared to pre-dose concentration (p ≤ 0.03)."}],"candidate_sources":[]},{"claim_id":"claim_10","claim":"Risk-of-bias honesty note: No populated per-source public appraisal ratings are reported in this artifact. Risk-of-bias language is therefore descriptive of source design and directness, not a claim that formal framework-specific scoring was completed.","citation_support":[],"candidate_sources":[{"study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","year":2025,"doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Wu 2025","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial","year":2025,"doi":"10.1002/lary.70173","url":"https://doi.org/10.1002/lary.70173","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Gao 2025","evidence_span":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p","excerpt":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p = 0.028). Tinnitus and aural fullness improved more in the NAD+ group, especially after 3 months.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","year":2020,"doi":"10.1186/s12882-020-02006-1","url":"https://doi.org/10.1186/s12882-020-02006-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Simic 2020","evidence_span":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was","excerpt":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD + response to treatment. Considering all Steps together, NRPT treatment increased NAD + levels by 37% at 48 h compared to 0 h ( p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. NRPT increases whole blood NAD + levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. NCT03176628 , date of registration June 5th, 2017. Keywords: Acute kidney injury, NAD + , Nicotinamide riboside, Pterostilbene, Safety study Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. AKI is most commonly diagnosed in patients following major invasive surgical procedures, in the setting of sepsis, or following administration of certain drugs or contrast dyes, particularly in patients with underlying hypertension, diabetes, or chronic kidney disease [ 1 ]. There is currently no specific treatment for AKI. Supportive measures include dialysis for patients with severe AKI, and mortality in this subset of patients exceeds 50% [ 2 ]. Thus, new preventive and treatment approaches are urgently needed. Nicotinamide adenine dinucleotide (NAD + ) is a key cellular factor linked to metabolism and longevity [ 3 ]. It is a required co-factor of SIRT1, a nuclear deacetylase that modulates chromatin structure, gene expression, extends lifespan in lower organisms, and improves many aging related diseases [ 4 , 5 ]. Experimental AKI in mice rapidly leads to the reduction of NAD + levels in the kidney that results from a combination of decreased NAD + biosynthesis and increased NAD + consumption [ 6 ]. NAD + augmentation by niacinamide has been shown to prevent various etiologies of experimental AKI in mice, and an initial pilot study has demonstrated the safety of niacinamide in patients undergoing cardiac surgery [ 7 ]. Further, mice deficient in SIRT1 are more susceptible to AKI and overexpression of SIRT1 protects from AKI [ 8 ]. These studies outline NAD + and SIRT1 modulation as a potential therapeutic approach in AKI [ 9 ]. Nicotinamide riboside with pterostilbene (NRPT) is a combination of nicotinamide riboside (NR), a form of vitamin B3, and pterostilbene (PT), a polyphenol found in blueberries [ 10 ]. NR is in wide use as an NAD + precursor, with distinct and superior pharmacokinetics to other NAD + intermediates in vitamin B metabolism such as nicotinic acid and niacinamide [ 11 ]. Through its effect on NAD + levels and SIRT1 activity, NR has been shown to have metabolic benefits and efficacy in a variety of disease models and to modestly increase lifespan in aged mice [ 12 ]. PT is a natural equivalent of the polyphenol resveratrol, an effective SIRT1 activator [ 13 ], that has greater bioavailability [ 14 ]. Therefore, the combination of NR and PT is predicted to have synergistic effect on metabolism, with NR augmenting NAD + levels and PT additionally activating SIRT1 [ 10 ]. NR supplementation alone has been studied in humans with cardiovascular [ 15 ], systemic metabolic [ 16 ], exercise [ 17 ], and muscle aging related end-points [ 18 ]. Further, NRPT has been evaluated in healthy elderly adults (age 60 to 80 years) and was shown to safely increase the blood concentration of NAD + in a dose-dependent manner by 40–90% [ 10 ]. To date, NR or NRPT have not been tested in patients with kidney disease. Thus, we sought to test the effect of escalating doses of NRPT on blood NAD+ levels and safety parameters in patients hospitalized with AKI, with the ultimate goal to test NRPT for the treatment of AKI. The incidence of AKI in hospitalized patients is about 1.6% with mortality rate of up to 35% [ 19 ]. AKI is associated with higher rates of death, subsequent hospitalization for stroke, heart failure, or myocardial infarction [ 20 ] and it accelerates the progression of CKD [ 21 ]. The management of patients with AKI is supportive, with renal replacement therapy indicated in patients with severe kidney injury. Currently, there are no specific therapeutics for the prevention and or management of AKI. Most studies in patients with AKI have focused on AKI after cardiac surgery, investigating renal perfusion, including studies investigating dopamine and neseritide, fenoldopam, aspirin or clonidine, buffered crystalloid, and remote ischemic preconditioning (reviewed in [ 22 ]), all to no avail. Trials examining the use of sodium bicarbonate or N-acetylcysteine in contrast induced nephropathy prevention have been inconclusive [ 23 ]. Because this prior focus on hemodynamics and perfusion has been unsuccessful, there has been increasing interest in augmenting kidney metabolic health by increasing NAD + levels and action as a novel therapeutic approach in AKI [ 7 , 9 ]. To our knowledge this is the first study describing whole blood NAD + levels in human AKI, with or without intervention. Across all treated individuals, NRPT treatment resulted in a significant increase in whole blood NAD + at 48 h. In placebo treated individuals, AKI resulted in a 50% decrease in whole blood NAD + levels at this time point. NRPT at all four tested doses was safe and well tolerated. These results motivate additional studies of NRPT as a potential therapeutic option in AKI. Our prespecified secondary endpoint was to determine the dose of NRPT that safely achieves at least a 50% increase (and up to a 100% increase) from baseline in cellular NAD + levels. The only dose of NRPT that resulted in a statistically significant increase in whole blood NAD + levels at 48 h as compared to 0 h was 500 mg/100 mg in Step 2, yielding a 47% increase. The Step 3 dose resulted in a 67% increase in whole blood NAD + levels that was not statistically significant. Thus in retrospect, the initial goal of a 50 to 100% increase in NAD + levels was likely set too high, in large part because it was based on studies in healthy volunteers [ 10 , 11 ] without accounting for such a profound decrease in whole blood NAD + levels with kidney injury (50% decrease after 2 days of AKI). NR alone was previously tested at similar doses (100, 300 and 1000 mg) in a study of 12 healthy volunteers, resulting in a significant increase in peripheral blood mononuclear cell NAD + levels after 24 h (all NR doses combined) and no effect during earlier time points (1, 2, 4 and 8 h) [ 11 ]. The relative increase in NAD + at 24 h vs 0 h was 46% for both 300 mg and 1000 mg of NR and only 12% for 100 mg of NR. NAD + was not measured beyond 24 h in this study [ 11 ]. We now show, in patients with AKI, a comparable increase in NAD + levels (40% at 48 h vs 0 h in all Steps combined), but with delayed effect to 48 h. This could represent slower incline in cellular NAD + in patients with AKI or the effect of PT. We have previously tested the combination of NR and PT (NRPT 250 mg/50 mg and 500 mg/100 mg) in 120 elderly healthy volunteers, with the focus on NAD + levels at later time points, namely after 30 and 60 days of treatment [ 10 ]. After 30 days of treatment, whole blood NAD + levels in the healthy elderly population increased by 40% in NRPT 250/50 mg and 90% in NRPT 500/100 mg treatment groups and the effect was sustained until 60 days [ 10 ]. In our study, NRPT at the same doses in an AKI population increased whole blood NAD + levels by 23 and 47% respectively at 48 h.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","year":2025,"doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Yu 2025","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","year":2021,"doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Connell 2021","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_11","claim":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text.","citation_support":[],"candidate_sources":[{"study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","year":2025,"doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Wu 2025","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial","year":2025,"doi":"10.1002/lary.70173","url":"https://doi.org/10.1002/lary.70173","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Gao 2025","evidence_span":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p","excerpt":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p = 0.028). Tinnitus and aural fullness improved more in the NAD+ group, especially after 3 months.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","year":2020,"doi":"10.1186/s12882-020-02006-1","url":"https://doi.org/10.1186/s12882-020-02006-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Simic 2020","evidence_span":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was","excerpt":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD + response to treatment. Considering all Steps together, NRPT treatment increased NAD + levels by 37% at 48 h compared to 0 h ( p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. NRPT increases whole blood NAD + levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. NCT03176628 , date of registration June 5th, 2017. Keywords: Acute kidney injury, NAD + , Nicotinamide riboside, Pterostilbene, Safety study Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. AKI is most commonly diagnosed in patients following major invasive surgical procedures, in the setting of sepsis, or following administration of certain drugs or contrast dyes, particularly in patients with underlying hypertension, diabetes, or chronic kidney disease [ 1 ]. There is currently no specific treatment for AKI. Supportive measures include dialysis for patients with severe AKI, and mortality in this subset of patients exceeds 50% [ 2 ]. Thus, new preventive and treatment approaches are urgently needed. Nicotinamide adenine dinucleotide (NAD + ) is a key cellular factor linked to metabolism and longevity [ 3 ]. It is a required co-factor of SIRT1, a nuclear deacetylase that modulates chromatin structure, gene expression, extends lifespan in lower organisms, and improves many aging related diseases [ 4 , 5 ]. Experimental AKI in mice rapidly leads to the reduction of NAD + levels in the kidney that results from a combination of decreased NAD + biosynthesis and increased NAD + consumption [ 6 ]. NAD + augmentation by niacinamide has been shown to prevent various etiologies of experimental AKI in mice, and an initial pilot study has demonstrated the safety of niacinamide in patients undergoing cardiac surgery [ 7 ]. Further, mice deficient in SIRT1 are more susceptible to AKI and overexpression of SIRT1 protects from AKI [ 8 ]. These studies outline NAD + and SIRT1 modulation as a potential therapeutic approach in AKI [ 9 ]. Nicotinamide riboside with pterostilbene (NRPT) is a combination of nicotinamide riboside (NR), a form of vitamin B3, and pterostilbene (PT), a polyphenol found in blueberries [ 10 ]. NR is in wide use as an NAD + precursor, with distinct and superior pharmacokinetics to other NAD + intermediates in vitamin B metabolism such as nicotinic acid and niacinamide [ 11 ]. Through its effect on NAD + levels and SIRT1 activity, NR has been shown to have metabolic benefits and efficacy in a variety of disease models and to modestly increase lifespan in aged mice [ 12 ]. PT is a natural equivalent of the polyphenol resveratrol, an effective SIRT1 activator [ 13 ], that has greater bioavailability [ 14 ]. Therefore, the combination of NR and PT is predicted to have synergistic effect on metabolism, with NR augmenting NAD + levels and PT additionally activating SIRT1 [ 10 ]. NR supplementation alone has been studied in humans with cardiovascular [ 15 ], systemic metabolic [ 16 ], exercise [ 17 ], and muscle aging related end-points [ 18 ]. Further, NRPT has been evaluated in healthy elderly adults (age 60 to 80 years) and was shown to safely increase the blood concentration of NAD + in a dose-dependent manner by 40–90% [ 10 ]. To date, NR or NRPT have not been tested in patients with kidney disease. Thus, we sought to test the effect of escalating doses of NRPT on blood NAD+ levels and safety parameters in patients hospitalized with AKI, with the ultimate goal to test NRPT for the treatment of AKI. The incidence of AKI in hospitalized patients is about 1.6% with mortality rate of up to 35% [ 19 ]. AKI is associated with higher rates of death, subsequent hospitalization for stroke, heart failure, or myocardial infarction [ 20 ] and it accelerates the progression of CKD [ 21 ]. The management of patients with AKI is supportive, with renal replacement therapy indicated in patients with severe kidney injury. Currently, there are no specific therapeutics for the prevention and or management of AKI. Most studies in patients with AKI have focused on AKI after cardiac surgery, investigating renal perfusion, including studies investigating dopamine and neseritide, fenoldopam, aspirin or clonidine, buffered crystalloid, and remote ischemic preconditioning (reviewed in [ 22 ]), all to no avail. Trials examining the use of sodium bicarbonate or N-acetylcysteine in contrast induced nephropathy prevention have been inconclusive [ 23 ]. Because this prior focus on hemodynamics and perfusion has been unsuccessful, there has been increasing interest in augmenting kidney metabolic health by increasing NAD + levels and action as a novel therapeutic approach in AKI [ 7 , 9 ]. To our knowledge this is the first study describing whole blood NAD + levels in human AKI, with or without intervention. Across all treated individuals, NRPT treatment resulted in a significant increase in whole blood NAD + at 48 h. In placebo treated individuals, AKI resulted in a 50% decrease in whole blood NAD + levels at this time point. NRPT at all four tested doses was safe and well tolerated. These results motivate additional studies of NRPT as a potential therapeutic option in AKI. Our prespecified secondary endpoint was to determine the dose of NRPT that safely achieves at least a 50% increase (and up to a 100% increase) from baseline in cellular NAD + levels. The only dose of NRPT that resulted in a statistically significant increase in whole blood NAD + levels at 48 h as compared to 0 h was 500 mg/100 mg in Step 2, yielding a 47% increase. The Step 3 dose resulted in a 67% increase in whole blood NAD + levels that was not statistically significant. Thus in retrospect, the initial goal of a 50 to 100% increase in NAD + levels was likely set too high, in large part because it was based on studies in healthy volunteers [ 10 , 11 ] without accounting for such a profound decrease in whole blood NAD + levels with kidney injury (50% decrease after 2 days of AKI). NR alone was previously tested at similar doses (100, 300 and 1000 mg) in a study of 12 healthy volunteers, resulting in a significant increase in peripheral blood mononuclear cell NAD + levels after 24 h (all NR doses combined) and no effect during earlier time points (1, 2, 4 and 8 h) [ 11 ]. The relative increase in NAD + at 24 h vs 0 h was 46% for both 300 mg and 1000 mg of NR and only 12% for 100 mg of NR. NAD + was not measured beyond 24 h in this study [ 11 ]. We now show, in patients with AKI, a comparable increase in NAD + levels (40% at 48 h vs 0 h in all Steps combined), but with delayed effect to 48 h. This could represent slower incline in cellular NAD + in patients with AKI or the effect of PT. We have previously tested the combination of NR and PT (NRPT 250 mg/50 mg and 500 mg/100 mg) in 120 elderly healthy volunteers, with the focus on NAD + levels at later time points, namely after 30 and 60 days of treatment [ 10 ]. After 30 days of treatment, whole blood NAD + levels in the healthy elderly population increased by 40% in NRPT 250/50 mg and 90% in NRPT 500/100 mg treatment groups and the effect was sustained until 60 days [ 10 ]. In our study, NRPT at the same doses in an AKI population increased whole blood NAD + levels by 23 and 47% respectively at 48 h.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","year":2025,"doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Yu 2025","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","year":2021,"doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Connell 2021","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_12","claim":"A source was coded as direct only when it tested the topic itself against a clinically proximate outcome in the relevant population. Human evidence with an adjacent exposure, population, or outcome was coded as indirect; syntheses and secondary reviews were coded as review-level evidence and were not counted as direct sources.","citation_support":[],"candidate_sources":[{"study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","year":2025,"doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Wu 2025","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial","year":2025,"doi":"10.1002/lary.70173","url":"https://doi.org/10.1002/lary.70173","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Gao 2025","evidence_span":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p","excerpt":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p = 0.028). Tinnitus and aural fullness improved more in the NAD+ group, especially after 3 months.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","year":2020,"doi":"10.1186/s12882-020-02006-1","url":"https://doi.org/10.1186/s12882-020-02006-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Simic 2020","evidence_span":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was","excerpt":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD + response to treatment. Considering all Steps together, NRPT treatment increased NAD + levels by 37% at 48 h compared to 0 h ( p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. NRPT increases whole blood NAD + levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. NCT03176628 , date of registration June 5th, 2017. Keywords: Acute kidney injury, NAD + , Nicotinamide riboside, Pterostilbene, Safety study Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. AKI is most commonly diagnosed in patients following major invasive surgical procedures, in the setting of sepsis, or following administration of certain drugs or contrast dyes, particularly in patients with underlying hypertension, diabetes, or chronic kidney disease [ 1 ]. There is currently no specific treatment for AKI. Supportive measures include dialysis for patients with severe AKI, and mortality in this subset of patients exceeds 50% [ 2 ]. Thus, new preventive and treatment approaches are urgently needed. Nicotinamide adenine dinucleotide (NAD + ) is a key cellular factor linked to metabolism and longevity [ 3 ]. It is a required co-factor of SIRT1, a nuclear deacetylase that modulates chromatin structure, gene expression, extends lifespan in lower organisms, and improves many aging related diseases [ 4 , 5 ]. Experimental AKI in mice rapidly leads to the reduction of NAD + levels in the kidney that results from a combination of decreased NAD + biosynthesis and increased NAD + consumption [ 6 ]. NAD + augmentation by niacinamide has been shown to prevent various etiologies of experimental AKI in mice, and an initial pilot study has demonstrated the safety of niacinamide in patients undergoing cardiac surgery [ 7 ]. Further, mice deficient in SIRT1 are more susceptible to AKI and overexpression of SIRT1 protects from AKI [ 8 ]. These studies outline NAD + and SIRT1 modulation as a potential therapeutic approach in AKI [ 9 ]. Nicotinamide riboside with pterostilbene (NRPT) is a combination of nicotinamide riboside (NR), a form of vitamin B3, and pterostilbene (PT), a polyphenol found in blueberries [ 10 ]. NR is in wide use as an NAD + precursor, with distinct and superior pharmacokinetics to other NAD + intermediates in vitamin B metabolism such as nicotinic acid and niacinamide [ 11 ]. Through its effect on NAD + levels and SIRT1 activity, NR has been shown to have metabolic benefits and efficacy in a variety of disease models and to modestly increase lifespan in aged mice [ 12 ]. PT is a natural equivalent of the polyphenol resveratrol, an effective SIRT1 activator [ 13 ], that has greater bioavailability [ 14 ]. Therefore, the combination of NR and PT is predicted to have synergistic effect on metabolism, with NR augmenting NAD + levels and PT additionally activating SIRT1 [ 10 ]. NR supplementation alone has been studied in humans with cardiovascular [ 15 ], systemic metabolic [ 16 ], exercise [ 17 ], and muscle aging related end-points [ 18 ]. Further, NRPT has been evaluated in healthy elderly adults (age 60 to 80 years) and was shown to safely increase the blood concentration of NAD + in a dose-dependent manner by 40–90% [ 10 ]. To date, NR or NRPT have not been tested in patients with kidney disease. Thus, we sought to test the effect of escalating doses of NRPT on blood NAD+ levels and safety parameters in patients hospitalized with AKI, with the ultimate goal to test NRPT for the treatment of AKI. The incidence of AKI in hospitalized patients is about 1.6% with mortality rate of up to 35% [ 19 ]. AKI is associated with higher rates of death, subsequent hospitalization for stroke, heart failure, or myocardial infarction [ 20 ] and it accelerates the progression of CKD [ 21 ]. The management of patients with AKI is supportive, with renal replacement therapy indicated in patients with severe kidney injury. Currently, there are no specific therapeutics for the prevention and or management of AKI. Most studies in patients with AKI have focused on AKI after cardiac surgery, investigating renal perfusion, including studies investigating dopamine and neseritide, fenoldopam, aspirin or clonidine, buffered crystalloid, and remote ischemic preconditioning (reviewed in [ 22 ]), all to no avail. Trials examining the use of sodium bicarbonate or N-acetylcysteine in contrast induced nephropathy prevention have been inconclusive [ 23 ]. Because this prior focus on hemodynamics and perfusion has been unsuccessful, there has been increasing interest in augmenting kidney metabolic health by increasing NAD + levels and action as a novel therapeutic approach in AKI [ 7 , 9 ]. To our knowledge this is the first study describing whole blood NAD + levels in human AKI, with or without intervention. Across all treated individuals, NRPT treatment resulted in a significant increase in whole blood NAD + at 48 h. In placebo treated individuals, AKI resulted in a 50% decrease in whole blood NAD + levels at this time point. NRPT at all four tested doses was safe and well tolerated. These results motivate additional studies of NRPT as a potential therapeutic option in AKI. Our prespecified secondary endpoint was to determine the dose of NRPT that safely achieves at least a 50% increase (and up to a 100% increase) from baseline in cellular NAD + levels. The only dose of NRPT that resulted in a statistically significant increase in whole blood NAD + levels at 48 h as compared to 0 h was 500 mg/100 mg in Step 2, yielding a 47% increase. The Step 3 dose resulted in a 67% increase in whole blood NAD + levels that was not statistically significant. Thus in retrospect, the initial goal of a 50 to 100% increase in NAD + levels was likely set too high, in large part because it was based on studies in healthy volunteers [ 10 , 11 ] without accounting for such a profound decrease in whole blood NAD + levels with kidney injury (50% decrease after 2 days of AKI). NR alone was previously tested at similar doses (100, 300 and 1000 mg) in a study of 12 healthy volunteers, resulting in a significant increase in peripheral blood mononuclear cell NAD + levels after 24 h (all NR doses combined) and no effect during earlier time points (1, 2, 4 and 8 h) [ 11 ]. The relative increase in NAD + at 24 h vs 0 h was 46% for both 300 mg and 1000 mg of NR and only 12% for 100 mg of NR. NAD + was not measured beyond 24 h in this study [ 11 ]. We now show, in patients with AKI, a comparable increase in NAD + levels (40% at 48 h vs 0 h in all Steps combined), but with delayed effect to 48 h. This could represent slower incline in cellular NAD + in patients with AKI or the effect of PT. We have previously tested the combination of NR and PT (NRPT 250 mg/50 mg and 500 mg/100 mg) in 120 elderly healthy volunteers, with the focus on NAD + levels at later time points, namely after 30 and 60 days of treatment [ 10 ]. After 30 days of treatment, whole blood NAD + levels in the healthy elderly population increased by 40% in NRPT 250/50 mg and 90% in NRPT 500/100 mg treatment groups and the effect was sustained until 60 days [ 10 ]. In our study, NRPT at the same doses in an AKI population increased whole blood NAD + levels by 23 and 47% respectively at 48 h.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","year":2025,"doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Yu 2025","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","year":2021,"doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Connell 2021","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_13","claim":"Risk-of-bias framework assignment follows study design (risk-of-bias appraisal for RCTs, non-randomized-study appraisal for non-randomised studies, review-quality appraisal for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.","citation_support":[],"candidate_sources":[{"study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","year":2025,"doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Wu 2025","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial","year":2025,"doi":"10.1002/lary.70173","url":"https://doi.org/10.1002/lary.70173","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Gao 2025","evidence_span":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p","excerpt":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p = 0.028). Tinnitus and aural fullness improved more in the NAD+ group, especially after 3 months.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","year":2020,"doi":"10.1186/s12882-020-02006-1","url":"https://doi.org/10.1186/s12882-020-02006-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Simic 2020","evidence_span":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was","excerpt":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD + response to treatment. Considering all Steps together, NRPT treatment increased NAD + levels by 37% at 48 h compared to 0 h ( p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. NRPT increases whole blood NAD + levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. NCT03176628 , date of registration June 5th, 2017. Keywords: Acute kidney injury, NAD + , Nicotinamide riboside, Pterostilbene, Safety study Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. AKI is most commonly diagnosed in patients following major invasive surgical procedures, in the setting of sepsis, or following administration of certain drugs or contrast dyes, particularly in patients with underlying hypertension, diabetes, or chronic kidney disease [ 1 ]. There is currently no specific treatment for AKI. Supportive measures include dialysis for patients with severe AKI, and mortality in this subset of patients exceeds 50% [ 2 ]. Thus, new preventive and treatment approaches are urgently needed. Nicotinamide adenine dinucleotide (NAD + ) is a key cellular factor linked to metabolism and longevity [ 3 ]. It is a required co-factor of SIRT1, a nuclear deacetylase that modulates chromatin structure, gene expression, extends lifespan in lower organisms, and improves many aging related diseases [ 4 , 5 ]. Experimental AKI in mice rapidly leads to the reduction of NAD + levels in the kidney that results from a combination of decreased NAD + biosynthesis and increased NAD + consumption [ 6 ]. NAD + augmentation by niacinamide has been shown to prevent various etiologies of experimental AKI in mice, and an initial pilot study has demonstrated the safety of niacinamide in patients undergoing cardiac surgery [ 7 ]. Further, mice deficient in SIRT1 are more susceptible to AKI and overexpression of SIRT1 protects from AKI [ 8 ]. These studies outline NAD + and SIRT1 modulation as a potential therapeutic approach in AKI [ 9 ]. Nicotinamide riboside with pterostilbene (NRPT) is a combination of nicotinamide riboside (NR), a form of vitamin B3, and pterostilbene (PT), a polyphenol found in blueberries [ 10 ]. NR is in wide use as an NAD + precursor, with distinct and superior pharmacokinetics to other NAD + intermediates in vitamin B metabolism such as nicotinic acid and niacinamide [ 11 ]. Through its effect on NAD + levels and SIRT1 activity, NR has been shown to have metabolic benefits and efficacy in a variety of disease models and to modestly increase lifespan in aged mice [ 12 ]. PT is a natural equivalent of the polyphenol resveratrol, an effective SIRT1 activator [ 13 ], that has greater bioavailability [ 14 ]. Therefore, the combination of NR and PT is predicted to have synergistic effect on metabolism, with NR augmenting NAD + levels and PT additionally activating SIRT1 [ 10 ]. NR supplementation alone has been studied in humans with cardiovascular [ 15 ], systemic metabolic [ 16 ], exercise [ 17 ], and muscle aging related end-points [ 18 ]. Further, NRPT has been evaluated in healthy elderly adults (age 60 to 80 years) and was shown to safely increase the blood concentration of NAD + in a dose-dependent manner by 40–90% [ 10 ]. To date, NR or NRPT have not been tested in patients with kidney disease. Thus, we sought to test the effect of escalating doses of NRPT on blood NAD+ levels and safety parameters in patients hospitalized with AKI, with the ultimate goal to test NRPT for the treatment of AKI. The incidence of AKI in hospitalized patients is about 1.6% with mortality rate of up to 35% [ 19 ]. AKI is associated with higher rates of death, subsequent hospitalization for stroke, heart failure, or myocardial infarction [ 20 ] and it accelerates the progression of CKD [ 21 ]. The management of patients with AKI is supportive, with renal replacement therapy indicated in patients with severe kidney injury. Currently, there are no specific therapeutics for the prevention and or management of AKI. Most studies in patients with AKI have focused on AKI after cardiac surgery, investigating renal perfusion, including studies investigating dopamine and neseritide, fenoldopam, aspirin or clonidine, buffered crystalloid, and remote ischemic preconditioning (reviewed in [ 22 ]), all to no avail. Trials examining the use of sodium bicarbonate or N-acetylcysteine in contrast induced nephropathy prevention have been inconclusive [ 23 ]. Because this prior focus on hemodynamics and perfusion has been unsuccessful, there has been increasing interest in augmenting kidney metabolic health by increasing NAD + levels and action as a novel therapeutic approach in AKI [ 7 , 9 ]. To our knowledge this is the first study describing whole blood NAD + levels in human AKI, with or without intervention. Across all treated individuals, NRPT treatment resulted in a significant increase in whole blood NAD + at 48 h. In placebo treated individuals, AKI resulted in a 50% decrease in whole blood NAD + levels at this time point. NRPT at all four tested doses was safe and well tolerated. These results motivate additional studies of NRPT as a potential therapeutic option in AKI. Our prespecified secondary endpoint was to determine the dose of NRPT that safely achieves at least a 50% increase (and up to a 100% increase) from baseline in cellular NAD + levels. The only dose of NRPT that resulted in a statistically significant increase in whole blood NAD + levels at 48 h as compared to 0 h was 500 mg/100 mg in Step 2, yielding a 47% increase. The Step 3 dose resulted in a 67% increase in whole blood NAD + levels that was not statistically significant. Thus in retrospect, the initial goal of a 50 to 100% increase in NAD + levels was likely set too high, in large part because it was based on studies in healthy volunteers [ 10 , 11 ] without accounting for such a profound decrease in whole blood NAD + levels with kidney injury (50% decrease after 2 days of AKI). NR alone was previously tested at similar doses (100, 300 and 1000 mg) in a study of 12 healthy volunteers, resulting in a significant increase in peripheral blood mononuclear cell NAD + levels after 24 h (all NR doses combined) and no effect during earlier time points (1, 2, 4 and 8 h) [ 11 ]. The relative increase in NAD + at 24 h vs 0 h was 46% for both 300 mg and 1000 mg of NR and only 12% for 100 mg of NR. NAD + was not measured beyond 24 h in this study [ 11 ]. We now show, in patients with AKI, a comparable increase in NAD + levels (40% at 48 h vs 0 h in all Steps combined), but with delayed effect to 48 h. This could represent slower incline in cellular NAD + in patients with AKI or the effect of PT. We have previously tested the combination of NR and PT (NRPT 250 mg/50 mg and 500 mg/100 mg) in 120 elderly healthy volunteers, with the focus on NAD + levels at later time points, namely after 30 and 60 days of treatment [ 10 ]. After 30 days of treatment, whole blood NAD + levels in the healthy elderly population increased by 40% in NRPT 250/50 mg and 90% in NRPT 500/100 mg treatment groups and the effect was sustained until 60 days [ 10 ]. In our study, NRPT at the same doses in an AKI population increased whole blood NAD + levels by 23 and 47% respectively at 48 h.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","year":2025,"doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Yu 2025","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","year":2021,"doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Connell 2021","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_14","claim":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, muscle function, safety and comorbidity); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.","citation_support":[],"candidate_sources":[{"study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","year":2025,"doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Wu 2025","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial","year":2025,"doi":"10.1002/lary.70173","url":"https://doi.org/10.1002/lary.70173","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Gao 2025","evidence_span":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p","excerpt":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p = 0.028). Tinnitus and aural fullness improved more in the NAD+ group, especially after 3 months.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","year":2020,"doi":"10.1186/s12882-020-02006-1","url":"https://doi.org/10.1186/s12882-020-02006-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Simic 2020","evidence_span":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was","excerpt":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD + response to treatment. Considering all Steps together, NRPT treatment increased NAD + levels by 37% at 48 h compared to 0 h ( p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. NRPT increases whole blood NAD + levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. NCT03176628 , date of registration June 5th, 2017. Keywords: Acute kidney injury, NAD + , Nicotinamide riboside, Pterostilbene, Safety study Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. AKI is most commonly diagnosed in patients following major invasive surgical procedures, in the setting of sepsis, or following administration of certain drugs or contrast dyes, particularly in patients with underlying hypertension, diabetes, or chronic kidney disease [ 1 ]. There is currently no specific treatment for AKI. Supportive measures include dialysis for patients with severe AKI, and mortality in this subset of patients exceeds 50% [ 2 ]. Thus, new preventive and treatment approaches are urgently needed. Nicotinamide adenine dinucleotide (NAD + ) is a key cellular factor linked to metabolism and longevity [ 3 ]. It is a required co-factor of SIRT1, a nuclear deacetylase that modulates chromatin structure, gene expression, extends lifespan in lower organisms, and improves many aging related diseases [ 4 , 5 ]. Experimental AKI in mice rapidly leads to the reduction of NAD + levels in the kidney that results from a combination of decreased NAD + biosynthesis and increased NAD + consumption [ 6 ]. NAD + augmentation by niacinamide has been shown to prevent various etiologies of experimental AKI in mice, and an initial pilot study has demonstrated the safety of niacinamide in patients undergoing cardiac surgery [ 7 ]. Further, mice deficient in SIRT1 are more susceptible to AKI and overexpression of SIRT1 protects from AKI [ 8 ]. These studies outline NAD + and SIRT1 modulation as a potential therapeutic approach in AKI [ 9 ]. Nicotinamide riboside with pterostilbene (NRPT) is a combination of nicotinamide riboside (NR), a form of vitamin B3, and pterostilbene (PT), a polyphenol found in blueberries [ 10 ]. NR is in wide use as an NAD + precursor, with distinct and superior pharmacokinetics to other NAD + intermediates in vitamin B metabolism such as nicotinic acid and niacinamide [ 11 ]. Through its effect on NAD + levels and SIRT1 activity, NR has been shown to have metabolic benefits and efficacy in a variety of disease models and to modestly increase lifespan in aged mice [ 12 ]. PT is a natural equivalent of the polyphenol resveratrol, an effective SIRT1 activator [ 13 ], that has greater bioavailability [ 14 ]. Therefore, the combination of NR and PT is predicted to have synergistic effect on metabolism, with NR augmenting NAD + levels and PT additionally activating SIRT1 [ 10 ]. NR supplementation alone has been studied in humans with cardiovascular [ 15 ], systemic metabolic [ 16 ], exercise [ 17 ], and muscle aging related end-points [ 18 ]. Further, NRPT has been evaluated in healthy elderly adults (age 60 to 80 years) and was shown to safely increase the blood concentration of NAD + in a dose-dependent manner by 40–90% [ 10 ]. To date, NR or NRPT have not been tested in patients with kidney disease. Thus, we sought to test the effect of escalating doses of NRPT on blood NAD+ levels and safety parameters in patients hospitalized with AKI, with the ultimate goal to test NRPT for the treatment of AKI. The incidence of AKI in hospitalized patients is about 1.6% with mortality rate of up to 35% [ 19 ]. AKI is associated with higher rates of death, subsequent hospitalization for stroke, heart failure, or myocardial infarction [ 20 ] and it accelerates the progression of CKD [ 21 ]. The management of patients with AKI is supportive, with renal replacement therapy indicated in patients with severe kidney injury. Currently, there are no specific therapeutics for the prevention and or management of AKI. Most studies in patients with AKI have focused on AKI after cardiac surgery, investigating renal perfusion, including studies investigating dopamine and neseritide, fenoldopam, aspirin or clonidine, buffered crystalloid, and remote ischemic preconditioning (reviewed in [ 22 ]), all to no avail. Trials examining the use of sodium bicarbonate or N-acetylcysteine in contrast induced nephropathy prevention have been inconclusive [ 23 ]. Because this prior focus on hemodynamics and perfusion has been unsuccessful, there has been increasing interest in augmenting kidney metabolic health by increasing NAD + levels and action as a novel therapeutic approach in AKI [ 7 , 9 ]. To our knowledge this is the first study describing whole blood NAD + levels in human AKI, with or without intervention. Across all treated individuals, NRPT treatment resulted in a significant increase in whole blood NAD + at 48 h. In placebo treated individuals, AKI resulted in a 50% decrease in whole blood NAD + levels at this time point. NRPT at all four tested doses was safe and well tolerated. These results motivate additional studies of NRPT as a potential therapeutic option in AKI. Our prespecified secondary endpoint was to determine the dose of NRPT that safely achieves at least a 50% increase (and up to a 100% increase) from baseline in cellular NAD + levels. The only dose of NRPT that resulted in a statistically significant increase in whole blood NAD + levels at 48 h as compared to 0 h was 500 mg/100 mg in Step 2, yielding a 47% increase. The Step 3 dose resulted in a 67% increase in whole blood NAD + levels that was not statistically significant. Thus in retrospect, the initial goal of a 50 to 100% increase in NAD + levels was likely set too high, in large part because it was based on studies in healthy volunteers [ 10 , 11 ] without accounting for such a profound decrease in whole blood NAD + levels with kidney injury (50% decrease after 2 days of AKI). NR alone was previously tested at similar doses (100, 300 and 1000 mg) in a study of 12 healthy volunteers, resulting in a significant increase in peripheral blood mononuclear cell NAD + levels after 24 h (all NR doses combined) and no effect during earlier time points (1, 2, 4 and 8 h) [ 11 ]. The relative increase in NAD + at 24 h vs 0 h was 46% for both 300 mg and 1000 mg of NR and only 12% for 100 mg of NR. NAD + was not measured beyond 24 h in this study [ 11 ]. We now show, in patients with AKI, a comparable increase in NAD + levels (40% at 48 h vs 0 h in all Steps combined), but with delayed effect to 48 h. This could represent slower incline in cellular NAD + in patients with AKI or the effect of PT. We have previously tested the combination of NR and PT (NRPT 250 mg/50 mg and 500 mg/100 mg) in 120 elderly healthy volunteers, with the focus on NAD + levels at later time points, namely after 30 and 60 days of treatment [ 10 ]. After 30 days of treatment, whole blood NAD + levels in the healthy elderly population increased by 40% in NRPT 250/50 mg and 90% in NRPT 500/100 mg treatment groups and the effect was sustained until 60 days [ 10 ]. In our study, NRPT at the same doses in an AKI population increased whole blood NAD + levels by 23 and 47% respectively at 48 h.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","year":2025,"doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Yu 2025","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","year":2021,"doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Connell 2021","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_15","claim":"| Evidence domain | Corpus slice | Direction profile | Directness | Main limitation |","citation_support":[],"candidate_sources":[{"study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","year":2025,"doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Wu 2025","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial","year":2025,"doi":"10.1002/lary.70173","url":"https://doi.org/10.1002/lary.70173","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Gao 2025","evidence_span":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p","excerpt":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p = 0.028). Tinnitus and aural fullness improved more in the NAD+ group, especially after 3 months.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","year":2020,"doi":"10.1186/s12882-020-02006-1","url":"https://doi.org/10.1186/s12882-020-02006-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Simic 2020","evidence_span":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was","excerpt":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD + response to treatment. Considering all Steps together, NRPT treatment increased NAD + levels by 37% at 48 h compared to 0 h ( p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. NRPT increases whole blood NAD + levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. NCT03176628 , date of registration June 5th, 2017. Keywords: Acute kidney injury, NAD + , Nicotinamide riboside, Pterostilbene, Safety study Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. AKI is most commonly diagnosed in patients following major invasive surgical procedures, in the setting of sepsis, or following administration of certain drugs or contrast dyes, particularly in patients with underlying hypertension, diabetes, or chronic kidney disease [ 1 ]. There is currently no specific treatment for AKI. Supportive measures include dialysis for patients with severe AKI, and mortality in this subset of patients exceeds 50% [ 2 ]. Thus, new preventive and treatment approaches are urgently needed. Nicotinamide adenine dinucleotide (NAD + ) is a key cellular factor linked to metabolism and longevity [ 3 ]. It is a required co-factor of SIRT1, a nuclear deacetylase that modulates chromatin structure, gene expression, extends lifespan in lower organisms, and improves many aging related diseases [ 4 , 5 ]. Experimental AKI in mice rapidly leads to the reduction of NAD + levels in the kidney that results from a combination of decreased NAD + biosynthesis and increased NAD + consumption [ 6 ]. NAD + augmentation by niacinamide has been shown to prevent various etiologies of experimental AKI in mice, and an initial pilot study has demonstrated the safety of niacinamide in patients undergoing cardiac surgery [ 7 ]. Further, mice deficient in SIRT1 are more susceptible to AKI and overexpression of SIRT1 protects from AKI [ 8 ]. These studies outline NAD + and SIRT1 modulation as a potential therapeutic approach in AKI [ 9 ]. Nicotinamide riboside with pterostilbene (NRPT) is a combination of nicotinamide riboside (NR), a form of vitamin B3, and pterostilbene (PT), a polyphenol found in blueberries [ 10 ]. NR is in wide use as an NAD + precursor, with distinct and superior pharmacokinetics to other NAD + intermediates in vitamin B metabolism such as nicotinic acid and niacinamide [ 11 ]. Through its effect on NAD + levels and SIRT1 activity, NR has been shown to have metabolic benefits and efficacy in a variety of disease models and to modestly increase lifespan in aged mice [ 12 ]. PT is a natural equivalent of the polyphenol resveratrol, an effective SIRT1 activator [ 13 ], that has greater bioavailability [ 14 ]. Therefore, the combination of NR and PT is predicted to have synergistic effect on metabolism, with NR augmenting NAD + levels and PT additionally activating SIRT1 [ 10 ]. NR supplementation alone has been studied in humans with cardiovascular [ 15 ], systemic metabolic [ 16 ], exercise [ 17 ], and muscle aging related end-points [ 18 ]. Further, NRPT has been evaluated in healthy elderly adults (age 60 to 80 years) and was shown to safely increase the blood concentration of NAD + in a dose-dependent manner by 40–90% [ 10 ]. To date, NR or NRPT have not been tested in patients with kidney disease. Thus, we sought to test the effect of escalating doses of NRPT on blood NAD+ levels and safety parameters in patients hospitalized with AKI, with the ultimate goal to test NRPT for the treatment of AKI. The incidence of AKI in hospitalized patients is about 1.6% with mortality rate of up to 35% [ 19 ]. AKI is associated with higher rates of death, subsequent hospitalization for stroke, heart failure, or myocardial infarction [ 20 ] and it accelerates the progression of CKD [ 21 ]. The management of patients with AKI is supportive, with renal replacement therapy indicated in patients with severe kidney injury. Currently, there are no specific therapeutics for the prevention and or management of AKI. Most studies in patients with AKI have focused on AKI after cardiac surgery, investigating renal perfusion, including studies investigating dopamine and neseritide, fenoldopam, aspirin or clonidine, buffered crystalloid, and remote ischemic preconditioning (reviewed in [ 22 ]), all to no avail. Trials examining the use of sodium bicarbonate or N-acetylcysteine in contrast induced nephropathy prevention have been inconclusive [ 23 ]. Because this prior focus on hemodynamics and perfusion has been unsuccessful, there has been increasing interest in augmenting kidney metabolic health by increasing NAD + levels and action as a novel therapeutic approach in AKI [ 7 , 9 ]. To our knowledge this is the first study describing whole blood NAD + levels in human AKI, with or without intervention. Across all treated individuals, NRPT treatment resulted in a significant increase in whole blood NAD + at 48 h. In placebo treated individuals, AKI resulted in a 50% decrease in whole blood NAD + levels at this time point. NRPT at all four tested doses was safe and well tolerated. These results motivate additional studies of NRPT as a potential therapeutic option in AKI. Our prespecified secondary endpoint was to determine the dose of NRPT that safely achieves at least a 50% increase (and up to a 100% increase) from baseline in cellular NAD + levels. The only dose of NRPT that resulted in a statistically significant increase in whole blood NAD + levels at 48 h as compared to 0 h was 500 mg/100 mg in Step 2, yielding a 47% increase. The Step 3 dose resulted in a 67% increase in whole blood NAD + levels that was not statistically significant. Thus in retrospect, the initial goal of a 50 to 100% increase in NAD + levels was likely set too high, in large part because it was based on studies in healthy volunteers [ 10 , 11 ] without accounting for such a profound decrease in whole blood NAD + levels with kidney injury (50% decrease after 2 days of AKI). NR alone was previously tested at similar doses (100, 300 and 1000 mg) in a study of 12 healthy volunteers, resulting in a significant increase in peripheral blood mononuclear cell NAD + levels after 24 h (all NR doses combined) and no effect during earlier time points (1, 2, 4 and 8 h) [ 11 ]. The relative increase in NAD + at 24 h vs 0 h was 46% for both 300 mg and 1000 mg of NR and only 12% for 100 mg of NR. NAD + was not measured beyond 24 h in this study [ 11 ]. We now show, in patients with AKI, a comparable increase in NAD + levels (40% at 48 h vs 0 h in all Steps combined), but with delayed effect to 48 h. This could represent slower incline in cellular NAD + in patients with AKI or the effect of PT. We have previously tested the combination of NR and PT (NRPT 250 mg/50 mg and 500 mg/100 mg) in 120 elderly healthy volunteers, with the focus on NAD + levels at later time points, namely after 30 and 60 days of treatment [ 10 ]. After 30 days of treatment, whole blood NAD + levels in the healthy elderly population increased by 40% in NRPT 250/50 mg and 90% in NRPT 500/100 mg treatment groups and the effect was sustained until 60 days [ 10 ]. In our study, NRPT at the same doses in an AKI population increased whole blood NAD + levels by 23 and 47% respectively at 48 h.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","year":2025,"doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Yu 2025","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","year":2021,"doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Connell 2021","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_16","claim":"| NAD+ Cardiovascular Effects / Contextual Adjacent Evidence | n=7; claims=174 | positive=0, negative=0, null=1, mixed=0, unclear=6 (n=7) | 7 direct | limited corpus depth in this outcome class |","citation_support":[],"candidate_sources":[{"study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","year":2025,"doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Wu 2025","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial","year":2025,"doi":"10.1002/lary.70173","url":"https://doi.org/10.1002/lary.70173","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Gao 2025","evidence_span":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p","excerpt":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p = 0.028). Tinnitus and aural fullness improved more in the NAD+ group, especially after 3 months.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","year":2020,"doi":"10.1186/s12882-020-02006-1","url":"https://doi.org/10.1186/s12882-020-02006-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Simic 2020","evidence_span":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was","excerpt":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD + response to treatment. Considering all Steps together, NRPT treatment increased NAD + levels by 37% at 48 h compared to 0 h ( p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. NRPT increases whole blood NAD + levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. NCT03176628 , date of registration June 5th, 2017. Keywords: Acute kidney injury, NAD + , Nicotinamide riboside, Pterostilbene, Safety study Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. AKI is most commonly diagnosed in patients following major invasive surgical procedures, in the setting of sepsis, or following administration of certain drugs or contrast dyes, particularly in patients with underlying hypertension, diabetes, or chronic kidney disease [ 1 ]. There is currently no specific treatment for AKI. Supportive measures include dialysis for patients with severe AKI, and mortality in this subset of patients exceeds 50% [ 2 ]. Thus, new preventive and treatment approaches are urgently needed. Nicotinamide adenine dinucleotide (NAD + ) is a key cellular factor linked to metabolism and longevity [ 3 ]. It is a required co-factor of SIRT1, a nuclear deacetylase that modulates chromatin structure, gene expression, extends lifespan in lower organisms, and improves many aging related diseases [ 4 , 5 ]. Experimental AKI in mice rapidly leads to the reduction of NAD + levels in the kidney that results from a combination of decreased NAD + biosynthesis and increased NAD + consumption [ 6 ]. NAD + augmentation by niacinamide has been shown to prevent various etiologies of experimental AKI in mice, and an initial pilot study has demonstrated the safety of niacinamide in patients undergoing cardiac surgery [ 7 ]. Further, mice deficient in SIRT1 are more susceptible to AKI and overexpression of SIRT1 protects from AKI [ 8 ]. These studies outline NAD + and SIRT1 modulation as a potential therapeutic approach in AKI [ 9 ]. Nicotinamide riboside with pterostilbene (NRPT) is a combination of nicotinamide riboside (NR), a form of vitamin B3, and pterostilbene (PT), a polyphenol found in blueberries [ 10 ]. NR is in wide use as an NAD + precursor, with distinct and superior pharmacokinetics to other NAD + intermediates in vitamin B metabolism such as nicotinic acid and niacinamide [ 11 ]. Through its effect on NAD + levels and SIRT1 activity, NR has been shown to have metabolic benefits and efficacy in a variety of disease models and to modestly increase lifespan in aged mice [ 12 ]. PT is a natural equivalent of the polyphenol resveratrol, an effective SIRT1 activator [ 13 ], that has greater bioavailability [ 14 ]. Therefore, the combination of NR and PT is predicted to have synergistic effect on metabolism, with NR augmenting NAD + levels and PT additionally activating SIRT1 [ 10 ]. NR supplementation alone has been studied in humans with cardiovascular [ 15 ], systemic metabolic [ 16 ], exercise [ 17 ], and muscle aging related end-points [ 18 ]. Further, NRPT has been evaluated in healthy elderly adults (age 60 to 80 years) and was shown to safely increase the blood concentration of NAD + in a dose-dependent manner by 40–90% [ 10 ]. To date, NR or NRPT have not been tested in patients with kidney disease. Thus, we sought to test the effect of escalating doses of NRPT on blood NAD+ levels and safety parameters in patients hospitalized with AKI, with the ultimate goal to test NRPT for the treatment of AKI. The incidence of AKI in hospitalized patients is about 1.6% with mortality rate of up to 35% [ 19 ]. AKI is associated with higher rates of death, subsequent hospitalization for stroke, heart failure, or myocardial infarction [ 20 ] and it accelerates the progression of CKD [ 21 ]. The management of patients with AKI is supportive, with renal replacement therapy indicated in patients with severe kidney injury. Currently, there are no specific therapeutics for the prevention and or management of AKI. Most studies in patients with AKI have focused on AKI after cardiac surgery, investigating renal perfusion, including studies investigating dopamine and neseritide, fenoldopam, aspirin or clonidine, buffered crystalloid, and remote ischemic preconditioning (reviewed in [ 22 ]), all to no avail. Trials examining the use of sodium bicarbonate or N-acetylcysteine in contrast induced nephropathy prevention have been inconclusive [ 23 ]. Because this prior focus on hemodynamics and perfusion has been unsuccessful, there has been increasing interest in augmenting kidney metabolic health by increasing NAD + levels and action as a novel therapeutic approach in AKI [ 7 , 9 ]. To our knowledge this is the first study describing whole blood NAD + levels in human AKI, with or without intervention. Across all treated individuals, NRPT treatment resulted in a significant increase in whole blood NAD + at 48 h. In placebo treated individuals, AKI resulted in a 50% decrease in whole blood NAD + levels at this time point. NRPT at all four tested doses was safe and well tolerated. These results motivate additional studies of NRPT as a potential therapeutic option in AKI. Our prespecified secondary endpoint was to determine the dose of NRPT that safely achieves at least a 50% increase (and up to a 100% increase) from baseline in cellular NAD + levels. The only dose of NRPT that resulted in a statistically significant increase in whole blood NAD + levels at 48 h as compared to 0 h was 500 mg/100 mg in Step 2, yielding a 47% increase. The Step 3 dose resulted in a 67% increase in whole blood NAD + levels that was not statistically significant. Thus in retrospect, the initial goal of a 50 to 100% increase in NAD + levels was likely set too high, in large part because it was based on studies in healthy volunteers [ 10 , 11 ] without accounting for such a profound decrease in whole blood NAD + levels with kidney injury (50% decrease after 2 days of AKI). NR alone was previously tested at similar doses (100, 300 and 1000 mg) in a study of 12 healthy volunteers, resulting in a significant increase in peripheral blood mononuclear cell NAD + levels after 24 h (all NR doses combined) and no effect during earlier time points (1, 2, 4 and 8 h) [ 11 ]. The relative increase in NAD + at 24 h vs 0 h was 46% for both 300 mg and 1000 mg of NR and only 12% for 100 mg of NR. NAD + was not measured beyond 24 h in this study [ 11 ]. We now show, in patients with AKI, a comparable increase in NAD + levels (40% at 48 h vs 0 h in all Steps combined), but with delayed effect to 48 h. This could represent slower incline in cellular NAD + in patients with AKI or the effect of PT. We have previously tested the combination of NR and PT (NRPT 250 mg/50 mg and 500 mg/100 mg) in 120 elderly healthy volunteers, with the focus on NAD + levels at later time points, namely after 30 and 60 days of treatment [ 10 ]. After 30 days of treatment, whole blood NAD + levels in the healthy elderly population increased by 40% in NRPT 250/50 mg and 90% in NRPT 500/100 mg treatment groups and the effect was sustained until 60 days [ 10 ]. In our study, NRPT at the same doses in an AKI population increased whole blood NAD + levels by 23 and 47% respectively at 48 h.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","year":2025,"doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Yu 2025","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","year":2021,"doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Connell 2021","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_17","claim":"| NAD+ Cardiovascular Effects / Muscle Function | n=4; claims=100 | positive=0, negative=1, null=1, mixed=0, unclear=2 (n=4) | 4 direct | limited corpus depth in this outcome class |","citation_support":[],"candidate_sources":[{"study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","year":2025,"doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Wu 2025","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial","year":2025,"doi":"10.1002/lary.70173","url":"https://doi.org/10.1002/lary.70173","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Gao 2025","evidence_span":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p","excerpt":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p = 0.028). Tinnitus and aural fullness improved more in the NAD+ group, especially after 3 months.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","year":2020,"doi":"10.1186/s12882-020-02006-1","url":"https://doi.org/10.1186/s12882-020-02006-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Simic 2020","evidence_span":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was","excerpt":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD + response to treatment. Considering all Steps together, NRPT treatment increased NAD + levels by 37% at 48 h compared to 0 h ( p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. NRPT increases whole blood NAD + levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. NCT03176628 , date of registration June 5th, 2017. Keywords: Acute kidney injury, NAD + , Nicotinamide riboside, Pterostilbene, Safety study Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. AKI is most commonly diagnosed in patients following major invasive surgical procedures, in the setting of sepsis, or following administration of certain drugs or contrast dyes, particularly in patients with underlying hypertension, diabetes, or chronic kidney disease [ 1 ]. There is currently no specific treatment for AKI. Supportive measures include dialysis for patients with severe AKI, and mortality in this subset of patients exceeds 50% [ 2 ]. Thus, new preventive and treatment approaches are urgently needed. Nicotinamide adenine dinucleotide (NAD + ) is a key cellular factor linked to metabolism and longevity [ 3 ]. It is a required co-factor of SIRT1, a nuclear deacetylase that modulates chromatin structure, gene expression, extends lifespan in lower organisms, and improves many aging related diseases [ 4 , 5 ]. Experimental AKI in mice rapidly leads to the reduction of NAD + levels in the kidney that results from a combination of decreased NAD + biosynthesis and increased NAD + consumption [ 6 ]. NAD + augmentation by niacinamide has been shown to prevent various etiologies of experimental AKI in mice, and an initial pilot study has demonstrated the safety of niacinamide in patients undergoing cardiac surgery [ 7 ]. Further, mice deficient in SIRT1 are more susceptible to AKI and overexpression of SIRT1 protects from AKI [ 8 ]. These studies outline NAD + and SIRT1 modulation as a potential therapeutic approach in AKI [ 9 ]. Nicotinamide riboside with pterostilbene (NRPT) is a combination of nicotinamide riboside (NR), a form of vitamin B3, and pterostilbene (PT), a polyphenol found in blueberries [ 10 ]. NR is in wide use as an NAD + precursor, with distinct and superior pharmacokinetics to other NAD + intermediates in vitamin B metabolism such as nicotinic acid and niacinamide [ 11 ]. Through its effect on NAD + levels and SIRT1 activity, NR has been shown to have metabolic benefits and efficacy in a variety of disease models and to modestly increase lifespan in aged mice [ 12 ]. PT is a natural equivalent of the polyphenol resveratrol, an effective SIRT1 activator [ 13 ], that has greater bioavailability [ 14 ]. Therefore, the combination of NR and PT is predicted to have synergistic effect on metabolism, with NR augmenting NAD + levels and PT additionally activating SIRT1 [ 10 ]. NR supplementation alone has been studied in humans with cardiovascular [ 15 ], systemic metabolic [ 16 ], exercise [ 17 ], and muscle aging related end-points [ 18 ]. Further, NRPT has been evaluated in healthy elderly adults (age 60 to 80 years) and was shown to safely increase the blood concentration of NAD + in a dose-dependent manner by 40–90% [ 10 ]. To date, NR or NRPT have not been tested in patients with kidney disease. Thus, we sought to test the effect of escalating doses of NRPT on blood NAD+ levels and safety parameters in patients hospitalized with AKI, with the ultimate goal to test NRPT for the treatment of AKI. The incidence of AKI in hospitalized patients is about 1.6% with mortality rate of up to 35% [ 19 ]. AKI is associated with higher rates of death, subsequent hospitalization for stroke, heart failure, or myocardial infarction [ 20 ] and it accelerates the progression of CKD [ 21 ]. The management of patients with AKI is supportive, with renal replacement therapy indicated in patients with severe kidney injury. Currently, there are no specific therapeutics for the prevention and or management of AKI. Most studies in patients with AKI have focused on AKI after cardiac surgery, investigating renal perfusion, including studies investigating dopamine and neseritide, fenoldopam, aspirin or clonidine, buffered crystalloid, and remote ischemic preconditioning (reviewed in [ 22 ]), all to no avail. Trials examining the use of sodium bicarbonate or N-acetylcysteine in contrast induced nephropathy prevention have been inconclusive [ 23 ]. Because this prior focus on hemodynamics and perfusion has been unsuccessful, there has been increasing interest in augmenting kidney metabolic health by increasing NAD + levels and action as a novel therapeutic approach in AKI [ 7 , 9 ]. To our knowledge this is the first study describing whole blood NAD + levels in human AKI, with or without intervention. Across all treated individuals, NRPT treatment resulted in a significant increase in whole blood NAD + at 48 h. In placebo treated individuals, AKI resulted in a 50% decrease in whole blood NAD + levels at this time point. NRPT at all four tested doses was safe and well tolerated. These results motivate additional studies of NRPT as a potential therapeutic option in AKI. Our prespecified secondary endpoint was to determine the dose of NRPT that safely achieves at least a 50% increase (and up to a 100% increase) from baseline in cellular NAD + levels. The only dose of NRPT that resulted in a statistically significant increase in whole blood NAD + levels at 48 h as compared to 0 h was 500 mg/100 mg in Step 2, yielding a 47% increase. The Step 3 dose resulted in a 67% increase in whole blood NAD + levels that was not statistically significant. Thus in retrospect, the initial goal of a 50 to 100% increase in NAD + levels was likely set too high, in large part because it was based on studies in healthy volunteers [ 10 , 11 ] without accounting for such a profound decrease in whole blood NAD + levels with kidney injury (50% decrease after 2 days of AKI). NR alone was previously tested at similar doses (100, 300 and 1000 mg) in a study of 12 healthy volunteers, resulting in a significant increase in peripheral blood mononuclear cell NAD + levels after 24 h (all NR doses combined) and no effect during earlier time points (1, 2, 4 and 8 h) [ 11 ]. The relative increase in NAD + at 24 h vs 0 h was 46% for both 300 mg and 1000 mg of NR and only 12% for 100 mg of NR. NAD + was not measured beyond 24 h in this study [ 11 ]. We now show, in patients with AKI, a comparable increase in NAD + levels (40% at 48 h vs 0 h in all Steps combined), but with delayed effect to 48 h. This could represent slower incline in cellular NAD + in patients with AKI or the effect of PT. We have previously tested the combination of NR and PT (NRPT 250 mg/50 mg and 500 mg/100 mg) in 120 elderly healthy volunteers, with the focus on NAD + levels at later time points, namely after 30 and 60 days of treatment [ 10 ]. After 30 days of treatment, whole blood NAD + levels in the healthy elderly population increased by 40% in NRPT 250/50 mg and 90% in NRPT 500/100 mg treatment groups and the effect was sustained until 60 days [ 10 ]. In our study, NRPT at the same doses in an AKI population increased whole blood NAD + levels by 23 and 47% respectively at 48 h.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","year":2025,"doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Yu 2025","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","year":2021,"doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Connell 2021","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_18","claim":"| NAD+ Cardiovascular Effects / Animal/Preclinical Context | n=2; claims=27 | positive=0, negative=0, null=0, mixed=0, unclear=2 (n=2) | 2 mechanistic | limited corpus depth in this outcome class |","citation_support":[],"candidate_sources":[{"study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","year":2025,"doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Wu 2025","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial","year":2025,"doi":"10.1002/lary.70173","url":"https://doi.org/10.1002/lary.70173","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Gao 2025","evidence_span":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p","excerpt":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p = 0.028). Tinnitus and aural fullness improved more in the NAD+ group, especially after 3 months.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","year":2020,"doi":"10.1186/s12882-020-02006-1","url":"https://doi.org/10.1186/s12882-020-02006-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Simic 2020","evidence_span":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was","excerpt":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD + response to treatment. Considering all Steps together, NRPT treatment increased NAD + levels by 37% at 48 h compared to 0 h ( p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. NRPT increases whole blood NAD + levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. NCT03176628 , date of registration June 5th, 2017. Keywords: Acute kidney injury, NAD + , Nicotinamide riboside, Pterostilbene, Safety study Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. AKI is most commonly diagnosed in patients following major invasive surgical procedures, in the setting of sepsis, or following administration of certain drugs or contrast dyes, particularly in patients with underlying hypertension, diabetes, or chronic kidney disease [ 1 ]. There is currently no specific treatment for AKI. Supportive measures include dialysis for patients with severe AKI, and mortality in this subset of patients exceeds 50% [ 2 ]. Thus, new preventive and treatment approaches are urgently needed. Nicotinamide adenine dinucleotide (NAD + ) is a key cellular factor linked to metabolism and longevity [ 3 ]. It is a required co-factor of SIRT1, a nuclear deacetylase that modulates chromatin structure, gene expression, extends lifespan in lower organisms, and improves many aging related diseases [ 4 , 5 ]. Experimental AKI in mice rapidly leads to the reduction of NAD + levels in the kidney that results from a combination of decreased NAD + biosynthesis and increased NAD + consumption [ 6 ]. NAD + augmentation by niacinamide has been shown to prevent various etiologies of experimental AKI in mice, and an initial pilot study has demonstrated the safety of niacinamide in patients undergoing cardiac surgery [ 7 ]. Further, mice deficient in SIRT1 are more susceptible to AKI and overexpression of SIRT1 protects from AKI [ 8 ]. These studies outline NAD + and SIRT1 modulation as a potential therapeutic approach in AKI [ 9 ]. Nicotinamide riboside with pterostilbene (NRPT) is a combination of nicotinamide riboside (NR), a form of vitamin B3, and pterostilbene (PT), a polyphenol found in blueberries [ 10 ]. NR is in wide use as an NAD + precursor, with distinct and superior pharmacokinetics to other NAD + intermediates in vitamin B metabolism such as nicotinic acid and niacinamide [ 11 ]. Through its effect on NAD + levels and SIRT1 activity, NR has been shown to have metabolic benefits and efficacy in a variety of disease models and to modestly increase lifespan in aged mice [ 12 ]. PT is a natural equivalent of the polyphenol resveratrol, an effective SIRT1 activator [ 13 ], that has greater bioavailability [ 14 ]. Therefore, the combination of NR and PT is predicted to have synergistic effect on metabolism, with NR augmenting NAD + levels and PT additionally activating SIRT1 [ 10 ]. NR supplementation alone has been studied in humans with cardiovascular [ 15 ], systemic metabolic [ 16 ], exercise [ 17 ], and muscle aging related end-points [ 18 ]. Further, NRPT has been evaluated in healthy elderly adults (age 60 to 80 years) and was shown to safely increase the blood concentration of NAD + in a dose-dependent manner by 40–90% [ 10 ]. To date, NR or NRPT have not been tested in patients with kidney disease. Thus, we sought to test the effect of escalating doses of NRPT on blood NAD+ levels and safety parameters in patients hospitalized with AKI, with the ultimate goal to test NRPT for the treatment of AKI. The incidence of AKI in hospitalized patients is about 1.6% with mortality rate of up to 35% [ 19 ]. AKI is associated with higher rates of death, subsequent hospitalization for stroke, heart failure, or myocardial infarction [ 20 ] and it accelerates the progression of CKD [ 21 ]. The management of patients with AKI is supportive, with renal replacement therapy indicated in patients with severe kidney injury. Currently, there are no specific therapeutics for the prevention and or management of AKI. Most studies in patients with AKI have focused on AKI after cardiac surgery, investigating renal perfusion, including studies investigating dopamine and neseritide, fenoldopam, aspirin or clonidine, buffered crystalloid, and remote ischemic preconditioning (reviewed in [ 22 ]), all to no avail. Trials examining the use of sodium bicarbonate or N-acetylcysteine in contrast induced nephropathy prevention have been inconclusive [ 23 ]. Because this prior focus on hemodynamics and perfusion has been unsuccessful, there has been increasing interest in augmenting kidney metabolic health by increasing NAD + levels and action as a novel therapeutic approach in AKI [ 7 , 9 ]. To our knowledge this is the first study describing whole blood NAD + levels in human AKI, with or without intervention. Across all treated individuals, NRPT treatment resulted in a significant increase in whole blood NAD + at 48 h. In placebo treated individuals, AKI resulted in a 50% decrease in whole blood NAD + levels at this time point. NRPT at all four tested doses was safe and well tolerated. These results motivate additional studies of NRPT as a potential therapeutic option in AKI. Our prespecified secondary endpoint was to determine the dose of NRPT that safely achieves at least a 50% increase (and up to a 100% increase) from baseline in cellular NAD + levels. The only dose of NRPT that resulted in a statistically significant increase in whole blood NAD + levels at 48 h as compared to 0 h was 500 mg/100 mg in Step 2, yielding a 47% increase. The Step 3 dose resulted in a 67% increase in whole blood NAD + levels that was not statistically significant. Thus in retrospect, the initial goal of a 50 to 100% increase in NAD + levels was likely set too high, in large part because it was based on studies in healthy volunteers [ 10 , 11 ] without accounting for such a profound decrease in whole blood NAD + levels with kidney injury (50% decrease after 2 days of AKI). NR alone was previously tested at similar doses (100, 300 and 1000 mg) in a study of 12 healthy volunteers, resulting in a significant increase in peripheral blood mononuclear cell NAD + levels after 24 h (all NR doses combined) and no effect during earlier time points (1, 2, 4 and 8 h) [ 11 ]. The relative increase in NAD + at 24 h vs 0 h was 46% for both 300 mg and 1000 mg of NR and only 12% for 100 mg of NR. NAD + was not measured beyond 24 h in this study [ 11 ]. We now show, in patients with AKI, a comparable increase in NAD + levels (40% at 48 h vs 0 h in all Steps combined), but with delayed effect to 48 h. This could represent slower incline in cellular NAD + in patients with AKI or the effect of PT. We have previously tested the combination of NR and PT (NRPT 250 mg/50 mg and 500 mg/100 mg) in 120 elderly healthy volunteers, with the focus on NAD + levels at later time points, namely after 30 and 60 days of treatment [ 10 ]. After 30 days of treatment, whole blood NAD + levels in the healthy elderly population increased by 40% in NRPT 250/50 mg and 90% in NRPT 500/100 mg treatment groups and the effect was sustained until 60 days [ 10 ]. In our study, NRPT at the same doses in an AKI population increased whole blood NAD + levels by 23 and 47% respectively at 48 h.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","year":2025,"doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Yu 2025","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","year":2021,"doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Connell 2021","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_19","claim":"| NAD+ Cardiovascular Effects / Safety and Comorbidity | n=2; claims=52 | positive=0, negative=0, null=0, mixed=1, unclear=1 (n=2) | 2 direct | limited corpus depth in this outcome class |","citation_support":[],"candidate_sources":[{"study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","year":2025,"doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Wu 2025","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial","year":2025,"doi":"10.1002/lary.70173","url":"https://doi.org/10.1002/lary.70173","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Gao 2025","evidence_span":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p","excerpt":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p = 0.028). Tinnitus and aural fullness improved more in the NAD+ group, especially after 3 months.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","year":2020,"doi":"10.1186/s12882-020-02006-1","url":"https://doi.org/10.1186/s12882-020-02006-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Simic 2020","evidence_span":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was","excerpt":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD + response to treatment. Considering all Steps together, NRPT treatment increased NAD + levels by 37% at 48 h compared to 0 h ( p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. NRPT increases whole blood NAD + levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. NCT03176628 , date of registration June 5th, 2017. Keywords: Acute kidney injury, NAD + , Nicotinamide riboside, Pterostilbene, Safety study Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. AKI is most commonly diagnosed in patients following major invasive surgical procedures, in the setting of sepsis, or following administration of certain drugs or contrast dyes, particularly in patients with underlying hypertension, diabetes, or chronic kidney disease [ 1 ]. There is currently no specific treatment for AKI. Supportive measures include dialysis for patients with severe AKI, and mortality in this subset of patients exceeds 50% [ 2 ]. Thus, new preventive and treatment approaches are urgently needed. Nicotinamide adenine dinucleotide (NAD + ) is a key cellular factor linked to metabolism and longevity [ 3 ]. It is a required co-factor of SIRT1, a nuclear deacetylase that modulates chromatin structure, gene expression, extends lifespan in lower organisms, and improves many aging related diseases [ 4 , 5 ]. Experimental AKI in mice rapidly leads to the reduction of NAD + levels in the kidney that results from a combination of decreased NAD + biosynthesis and increased NAD + consumption [ 6 ]. NAD + augmentation by niacinamide has been shown to prevent various etiologies of experimental AKI in mice, and an initial pilot study has demonstrated the safety of niacinamide in patients undergoing cardiac surgery [ 7 ]. Further, mice deficient in SIRT1 are more susceptible to AKI and overexpression of SIRT1 protects from AKI [ 8 ]. These studies outline NAD + and SIRT1 modulation as a potential therapeutic approach in AKI [ 9 ]. Nicotinamide riboside with pterostilbene (NRPT) is a combination of nicotinamide riboside (NR), a form of vitamin B3, and pterostilbene (PT), a polyphenol found in blueberries [ 10 ]. NR is in wide use as an NAD + precursor, with distinct and superior pharmacokinetics to other NAD + intermediates in vitamin B metabolism such as nicotinic acid and niacinamide [ 11 ]. Through its effect on NAD + levels and SIRT1 activity, NR has been shown to have metabolic benefits and efficacy in a variety of disease models and to modestly increase lifespan in aged mice [ 12 ]. PT is a natural equivalent of the polyphenol resveratrol, an effective SIRT1 activator [ 13 ], that has greater bioavailability [ 14 ]. Therefore, the combination of NR and PT is predicted to have synergistic effect on metabolism, with NR augmenting NAD + levels and PT additionally activating SIRT1 [ 10 ]. NR supplementation alone has been studied in humans with cardiovascular [ 15 ], systemic metabolic [ 16 ], exercise [ 17 ], and muscle aging related end-points [ 18 ]. Further, NRPT has been evaluated in healthy elderly adults (age 60 to 80 years) and was shown to safely increase the blood concentration of NAD + in a dose-dependent manner by 40–90% [ 10 ]. To date, NR or NRPT have not been tested in patients with kidney disease. Thus, we sought to test the effect of escalating doses of NRPT on blood NAD+ levels and safety parameters in patients hospitalized with AKI, with the ultimate goal to test NRPT for the treatment of AKI. The incidence of AKI in hospitalized patients is about 1.6% with mortality rate of up to 35% [ 19 ]. AKI is associated with higher rates of death, subsequent hospitalization for stroke, heart failure, or myocardial infarction [ 20 ] and it accelerates the progression of CKD [ 21 ]. The management of patients with AKI is supportive, with renal replacement therapy indicated in patients with severe kidney injury. Currently, there are no specific therapeutics for the prevention and or management of AKI. Most studies in patients with AKI have focused on AKI after cardiac surgery, investigating renal perfusion, including studies investigating dopamine and neseritide, fenoldopam, aspirin or clonidine, buffered crystalloid, and remote ischemic preconditioning (reviewed in [ 22 ]), all to no avail. Trials examining the use of sodium bicarbonate or N-acetylcysteine in contrast induced nephropathy prevention have been inconclusive [ 23 ]. Because this prior focus on hemodynamics and perfusion has been unsuccessful, there has been increasing interest in augmenting kidney metabolic health by increasing NAD + levels and action as a novel therapeutic approach in AKI [ 7 , 9 ]. To our knowledge this is the first study describing whole blood NAD + levels in human AKI, with or without intervention. Across all treated individuals, NRPT treatment resulted in a significant increase in whole blood NAD + at 48 h. In placebo treated individuals, AKI resulted in a 50% decrease in whole blood NAD + levels at this time point. NRPT at all four tested doses was safe and well tolerated. These results motivate additional studies of NRPT as a potential therapeutic option in AKI. Our prespecified secondary endpoint was to determine the dose of NRPT that safely achieves at least a 50% increase (and up to a 100% increase) from baseline in cellular NAD + levels. The only dose of NRPT that resulted in a statistically significant increase in whole blood NAD + levels at 48 h as compared to 0 h was 500 mg/100 mg in Step 2, yielding a 47% increase. The Step 3 dose resulted in a 67% increase in whole blood NAD + levels that was not statistically significant. Thus in retrospect, the initial goal of a 50 to 100% increase in NAD + levels was likely set too high, in large part because it was based on studies in healthy volunteers [ 10 , 11 ] without accounting for such a profound decrease in whole blood NAD + levels with kidney injury (50% decrease after 2 days of AKI). NR alone was previously tested at similar doses (100, 300 and 1000 mg) in a study of 12 healthy volunteers, resulting in a significant increase in peripheral blood mononuclear cell NAD + levels after 24 h (all NR doses combined) and no effect during earlier time points (1, 2, 4 and 8 h) [ 11 ]. The relative increase in NAD + at 24 h vs 0 h was 46% for both 300 mg and 1000 mg of NR and only 12% for 100 mg of NR. NAD + was not measured beyond 24 h in this study [ 11 ]. We now show, in patients with AKI, a comparable increase in NAD + levels (40% at 48 h vs 0 h in all Steps combined), but with delayed effect to 48 h. This could represent slower incline in cellular NAD + in patients with AKI or the effect of PT. We have previously tested the combination of NR and PT (NRPT 250 mg/50 mg and 500 mg/100 mg) in 120 elderly healthy volunteers, with the focus on NAD + levels at later time points, namely after 30 and 60 days of treatment [ 10 ]. After 30 days of treatment, whole blood NAD + levels in the healthy elderly population increased by 40% in NRPT 250/50 mg and 90% in NRPT 500/100 mg treatment groups and the effect was sustained until 60 days [ 10 ]. In our study, NRPT at the same doses in an AKI population increased whole blood NAD + levels by 23 and 47% respectively at 48 h.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","year":2025,"doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Yu 2025","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","year":2021,"doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Connell 2021","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_20","claim":"| NAD+ Cardiovascular Effects / Cardiometabolic | n=1; claims=13 | positive=0, negative=1, null=0, mixed=0, unclear=0 (n=1) | 1 direct | single-source slice; hypothesis-generating |","citation_support":[],"candidate_sources":[{"study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","year":2025,"doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Wu 2025","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial","year":2025,"doi":"10.1002/lary.70173","url":"https://doi.org/10.1002/lary.70173","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Gao 2025","evidence_span":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p","excerpt":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p = 0.028). Tinnitus and aural fullness improved more in the NAD+ group, especially after 3 months.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","year":2020,"doi":"10.1186/s12882-020-02006-1","url":"https://doi.org/10.1186/s12882-020-02006-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Simic 2020","evidence_span":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was","excerpt":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD + response to treatment. Considering all Steps together, NRPT treatment increased NAD + levels by 37% at 48 h compared to 0 h ( p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. NRPT increases whole blood NAD + levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. NCT03176628 , date of registration June 5th, 2017. Keywords: Acute kidney injury, NAD + , Nicotinamide riboside, Pterostilbene, Safety study Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. AKI is most commonly diagnosed in patients following major invasive surgical procedures, in the setting of sepsis, or following administration of certain drugs or contrast dyes, particularly in patients with underlying hypertension, diabetes, or chronic kidney disease [ 1 ]. There is currently no specific treatment for AKI. Supportive measures include dialysis for patients with severe AKI, and mortality in this subset of patients exceeds 50% [ 2 ]. Thus, new preventive and treatment approaches are urgently needed. Nicotinamide adenine dinucleotide (NAD + ) is a key cellular factor linked to metabolism and longevity [ 3 ]. It is a required co-factor of SIRT1, a nuclear deacetylase that modulates chromatin structure, gene expression, extends lifespan in lower organisms, and improves many aging related diseases [ 4 , 5 ]. Experimental AKI in mice rapidly leads to the reduction of NAD + levels in the kidney that results from a combination of decreased NAD + biosynthesis and increased NAD + consumption [ 6 ]. NAD + augmentation by niacinamide has been shown to prevent various etiologies of experimental AKI in mice, and an initial pilot study has demonstrated the safety of niacinamide in patients undergoing cardiac surgery [ 7 ]. Further, mice deficient in SIRT1 are more susceptible to AKI and overexpression of SIRT1 protects from AKI [ 8 ]. These studies outline NAD + and SIRT1 modulation as a potential therapeutic approach in AKI [ 9 ]. Nicotinamide riboside with pterostilbene (NRPT) is a combination of nicotinamide riboside (NR), a form of vitamin B3, and pterostilbene (PT), a polyphenol found in blueberries [ 10 ]. NR is in wide use as an NAD + precursor, with distinct and superior pharmacokinetics to other NAD + intermediates in vitamin B metabolism such as nicotinic acid and niacinamide [ 11 ]. Through its effect on NAD + levels and SIRT1 activity, NR has been shown to have metabolic benefits and efficacy in a variety of disease models and to modestly increase lifespan in aged mice [ 12 ]. PT is a natural equivalent of the polyphenol resveratrol, an effective SIRT1 activator [ 13 ], that has greater bioavailability [ 14 ]. Therefore, the combination of NR and PT is predicted to have synergistic effect on metabolism, with NR augmenting NAD + levels and PT additionally activating SIRT1 [ 10 ]. NR supplementation alone has been studied in humans with cardiovascular [ 15 ], systemic metabolic [ 16 ], exercise [ 17 ], and muscle aging related end-points [ 18 ]. Further, NRPT has been evaluated in healthy elderly adults (age 60 to 80 years) and was shown to safely increase the blood concentration of NAD + in a dose-dependent manner by 40–90% [ 10 ]. To date, NR or NRPT have not been tested in patients with kidney disease. Thus, we sought to test the effect of escalating doses of NRPT on blood NAD+ levels and safety parameters in patients hospitalized with AKI, with the ultimate goal to test NRPT for the treatment of AKI. The incidence of AKI in hospitalized patients is about 1.6% with mortality rate of up to 35% [ 19 ]. AKI is associated with higher rates of death, subsequent hospitalization for stroke, heart failure, or myocardial infarction [ 20 ] and it accelerates the progression of CKD [ 21 ]. The management of patients with AKI is supportive, with renal replacement therapy indicated in patients with severe kidney injury. Currently, there are no specific therapeutics for the prevention and or management of AKI. Most studies in patients with AKI have focused on AKI after cardiac surgery, investigating renal perfusion, including studies investigating dopamine and neseritide, fenoldopam, aspirin or clonidine, buffered crystalloid, and remote ischemic preconditioning (reviewed in [ 22 ]), all to no avail. Trials examining the use of sodium bicarbonate or N-acetylcysteine in contrast induced nephropathy prevention have been inconclusive [ 23 ]. Because this prior focus on hemodynamics and perfusion has been unsuccessful, there has been increasing interest in augmenting kidney metabolic health by increasing NAD + levels and action as a novel therapeutic approach in AKI [ 7 , 9 ]. To our knowledge this is the first study describing whole blood NAD + levels in human AKI, with or without intervention. Across all treated individuals, NRPT treatment resulted in a significant increase in whole blood NAD + at 48 h. In placebo treated individuals, AKI resulted in a 50% decrease in whole blood NAD + levels at this time point. NRPT at all four tested doses was safe and well tolerated. These results motivate additional studies of NRPT as a potential therapeutic option in AKI. Our prespecified secondary endpoint was to determine the dose of NRPT that safely achieves at least a 50% increase (and up to a 100% increase) from baseline in cellular NAD + levels. The only dose of NRPT that resulted in a statistically significant increase in whole blood NAD + levels at 48 h as compared to 0 h was 500 mg/100 mg in Step 2, yielding a 47% increase. The Step 3 dose resulted in a 67% increase in whole blood NAD + levels that was not statistically significant. Thus in retrospect, the initial goal of a 50 to 100% increase in NAD + levels was likely set too high, in large part because it was based on studies in healthy volunteers [ 10 , 11 ] without accounting for such a profound decrease in whole blood NAD + levels with kidney injury (50% decrease after 2 days of AKI). NR alone was previously tested at similar doses (100, 300 and 1000 mg) in a study of 12 healthy volunteers, resulting in a significant increase in peripheral blood mononuclear cell NAD + levels after 24 h (all NR doses combined) and no effect during earlier time points (1, 2, 4 and 8 h) [ 11 ]. The relative increase in NAD + at 24 h vs 0 h was 46% for both 300 mg and 1000 mg of NR and only 12% for 100 mg of NR. NAD + was not measured beyond 24 h in this study [ 11 ]. We now show, in patients with AKI, a comparable increase in NAD + levels (40% at 48 h vs 0 h in all Steps combined), but with delayed effect to 48 h. This could represent slower incline in cellular NAD + in patients with AKI or the effect of PT. We have previously tested the combination of NR and PT (NRPT 250 mg/50 mg and 500 mg/100 mg) in 120 elderly healthy volunteers, with the focus on NAD + levels at later time points, namely after 30 and 60 days of treatment [ 10 ]. After 30 days of treatment, whole blood NAD + levels in the healthy elderly population increased by 40% in NRPT 250/50 mg and 90% in NRPT 500/100 mg treatment groups and the effect was sustained until 60 days [ 10 ]. In our study, NRPT at the same doses in an AKI population increased whole blood NAD + levels by 23 and 47% respectively at 48 h.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","year":2025,"doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Yu 2025","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","year":2021,"doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Connell 2021","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_21","claim":"| NAD+ Cardiovascular Effects / Dosing and Pharmacokinetics | n=1; claims=29 | positive=0, negative=0, null=0, mixed=0, unclear=1 (n=1) | 1 direct | single-source slice; hypothesis-generating |","citation_support":[],"candidate_sources":[{"study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","year":2025,"doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Wu 2025","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial","year":2025,"doi":"10.1002/lary.70173","url":"https://doi.org/10.1002/lary.70173","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Gao 2025","evidence_span":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p","excerpt":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p = 0.028). Tinnitus and aural fullness improved more in the NAD+ group, especially after 3 months.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","year":2020,"doi":"10.1186/s12882-020-02006-1","url":"https://doi.org/10.1186/s12882-020-02006-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Simic 2020","evidence_span":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was","excerpt":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD + response to treatment. Considering all Steps together, NRPT treatment increased NAD + levels by 37% at 48 h compared to 0 h ( p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. NRPT increases whole blood NAD + levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. NCT03176628 , date of registration June 5th, 2017. Keywords: Acute kidney injury, NAD + , Nicotinamide riboside, Pterostilbene, Safety study Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. AKI is most commonly diagnosed in patients following major invasive surgical procedures, in the setting of sepsis, or following administration of certain drugs or contrast dyes, particularly in patients with underlying hypertension, diabetes, or chronic kidney disease [ 1 ]. There is currently no specific treatment for AKI. Supportive measures include dialysis for patients with severe AKI, and mortality in this subset of patients exceeds 50% [ 2 ]. Thus, new preventive and treatment approaches are urgently needed. Nicotinamide adenine dinucleotide (NAD + ) is a key cellular factor linked to metabolism and longevity [ 3 ]. It is a required co-factor of SIRT1, a nuclear deacetylase that modulates chromatin structure, gene expression, extends lifespan in lower organisms, and improves many aging related diseases [ 4 , 5 ]. Experimental AKI in mice rapidly leads to the reduction of NAD + levels in the kidney that results from a combination of decreased NAD + biosynthesis and increased NAD + consumption [ 6 ]. NAD + augmentation by niacinamide has been shown to prevent various etiologies of experimental AKI in mice, and an initial pilot study has demonstrated the safety of niacinamide in patients undergoing cardiac surgery [ 7 ]. Further, mice deficient in SIRT1 are more susceptible to AKI and overexpression of SIRT1 protects from AKI [ 8 ]. These studies outline NAD + and SIRT1 modulation as a potential therapeutic approach in AKI [ 9 ]. Nicotinamide riboside with pterostilbene (NRPT) is a combination of nicotinamide riboside (NR), a form of vitamin B3, and pterostilbene (PT), a polyphenol found in blueberries [ 10 ]. NR is in wide use as an NAD + precursor, with distinct and superior pharmacokinetics to other NAD + intermediates in vitamin B metabolism such as nicotinic acid and niacinamide [ 11 ]. Through its effect on NAD + levels and SIRT1 activity, NR has been shown to have metabolic benefits and efficacy in a variety of disease models and to modestly increase lifespan in aged mice [ 12 ]. PT is a natural equivalent of the polyphenol resveratrol, an effective SIRT1 activator [ 13 ], that has greater bioavailability [ 14 ]. Therefore, the combination of NR and PT is predicted to have synergistic effect on metabolism, with NR augmenting NAD + levels and PT additionally activating SIRT1 [ 10 ]. NR supplementation alone has been studied in humans with cardiovascular [ 15 ], systemic metabolic [ 16 ], exercise [ 17 ], and muscle aging related end-points [ 18 ]. Further, NRPT has been evaluated in healthy elderly adults (age 60 to 80 years) and was shown to safely increase the blood concentration of NAD + in a dose-dependent manner by 40–90% [ 10 ]. To date, NR or NRPT have not been tested in patients with kidney disease. Thus, we sought to test the effect of escalating doses of NRPT on blood NAD+ levels and safety parameters in patients hospitalized with AKI, with the ultimate goal to test NRPT for the treatment of AKI. The incidence of AKI in hospitalized patients is about 1.6% with mortality rate of up to 35% [ 19 ]. AKI is associated with higher rates of death, subsequent hospitalization for stroke, heart failure, or myocardial infarction [ 20 ] and it accelerates the progression of CKD [ 21 ]. The management of patients with AKI is supportive, with renal replacement therapy indicated in patients with severe kidney injury. Currently, there are no specific therapeutics for the prevention and or management of AKI. Most studies in patients with AKI have focused on AKI after cardiac surgery, investigating renal perfusion, including studies investigating dopamine and neseritide, fenoldopam, aspirin or clonidine, buffered crystalloid, and remote ischemic preconditioning (reviewed in [ 22 ]), all to no avail. Trials examining the use of sodium bicarbonate or N-acetylcysteine in contrast induced nephropathy prevention have been inconclusive [ 23 ]. Because this prior focus on hemodynamics and perfusion has been unsuccessful, there has been increasing interest in augmenting kidney metabolic health by increasing NAD + levels and action as a novel therapeutic approach in AKI [ 7 , 9 ]. To our knowledge this is the first study describing whole blood NAD + levels in human AKI, with or without intervention. Across all treated individuals, NRPT treatment resulted in a significant increase in whole blood NAD + at 48 h. In placebo treated individuals, AKI resulted in a 50% decrease in whole blood NAD + levels at this time point. NRPT at all four tested doses was safe and well tolerated. These results motivate additional studies of NRPT as a potential therapeutic option in AKI. Our prespecified secondary endpoint was to determine the dose of NRPT that safely achieves at least a 50% increase (and up to a 100% increase) from baseline in cellular NAD + levels. The only dose of NRPT that resulted in a statistically significant increase in whole blood NAD + levels at 48 h as compared to 0 h was 500 mg/100 mg in Step 2, yielding a 47% increase. The Step 3 dose resulted in a 67% increase in whole blood NAD + levels that was not statistically significant. Thus in retrospect, the initial goal of a 50 to 100% increase in NAD + levels was likely set too high, in large part because it was based on studies in healthy volunteers [ 10 , 11 ] without accounting for such a profound decrease in whole blood NAD + levels with kidney injury (50% decrease after 2 days of AKI). NR alone was previously tested at similar doses (100, 300 and 1000 mg) in a study of 12 healthy volunteers, resulting in a significant increase in peripheral blood mononuclear cell NAD + levels after 24 h (all NR doses combined) and no effect during earlier time points (1, 2, 4 and 8 h) [ 11 ]. The relative increase in NAD + at 24 h vs 0 h was 46% for both 300 mg and 1000 mg of NR and only 12% for 100 mg of NR. NAD + was not measured beyond 24 h in this study [ 11 ]. We now show, in patients with AKI, a comparable increase in NAD + levels (40% at 48 h vs 0 h in all Steps combined), but with delayed effect to 48 h. This could represent slower incline in cellular NAD + in patients with AKI or the effect of PT. We have previously tested the combination of NR and PT (NRPT 250 mg/50 mg and 500 mg/100 mg) in 120 elderly healthy volunteers, with the focus on NAD + levels at later time points, namely after 30 and 60 days of treatment [ 10 ]. After 30 days of treatment, whole blood NAD + levels in the healthy elderly population increased by 40% in NRPT 250/50 mg and 90% in NRPT 500/100 mg treatment groups and the effect was sustained until 60 days [ 10 ]. In our study, NRPT at the same doses in an AKI population increased whole blood NAD + levels by 23 and 47% respectively at 48 h.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","year":2025,"doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Yu 2025","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","year":2021,"doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Connell 2021","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_22","claim":"Wu 2025 [bundle:1] (Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled; representative statistic P < 0.001; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=null; directness=direct; tier=A1).","citation_support":[{"source_id":"source_1","study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","support_kind":"bundle_reference","cited_as":"Wu 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig."}],"candidate_sources":[]},{"claim_id":"claim_23","claim":"Gao 2025 [bundle:2] (NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial; representative statistic P = 0.030; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1).","citation_support":[{"source_id":"source_2","study":"NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial","doi":"10.1002/lary.70173","url":"https://doi.org/10.1002/lary.70173","support_kind":"bundle_reference","cited_as":"Gao 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p","excerpt":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p = 0.028). Tinnitus and aural fullness improved more in the NAD+ group, especially after 3 months."}],"candidate_sources":[]},{"claim_id":"claim_24","claim":"Xue 2022 [bundle:7] (A Combination of Nicotinamide and D-Ribose (RiaGev) Is Safe and Effective to Increase NAD + Metabolome in Healthy; representative statistic P = 0.033; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1).","citation_support":[{"source_id":"source_7","study":"A Combination of Nicotinamide and D-Ribose (RiaGev) Is Safe and Effective to Increase NAD + Metabolome in Healthy Middle-Aged Adults: A Randomized, Triple-Blind, Placebo-Controlled, Cross-Over Pilot Clinical Trial","doi":"10.3390/nu14112219","url":"https://doi.org/10.3390/nu14112219","support_kind":"bundle_reference","cited_as":"Xue 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"Supplementing with 1520 mg RiaGev twice daily for 7 days significantly increased the NAD + metabolome in blood, especially NADP + by 27% compared to the placebo group ( p = 0.033) and over the baseline ( p = 0.007). Increases in glutathione and high energy phosphates were also observed in the blood. Seven-day supplementation with RiaGev significantly ( p = 0.013) reduced overall blood glucose without significant changes in insulin secretion ( p = 0.796), suggesting an improved insulin sensitivity and glucose tolerance. The waking salivary cortisol of the subjects steadily and significantly","excerpt":"Supplementing with 1520 mg RiaGev twice daily for 7 days significantly increased the NAD + metabolome in blood, especially NADP + by 27% compared to the placebo group ( p = 0.033) and over the baseline ( p = 0.007). Increases in glutathione and high energy phosphates were also observed in the blood. Seven-day supplementation with RiaGev significantly ( p = 0.013) reduced overall blood glucose without significant changes in insulin secretion ( p = 0.796), suggesting an improved insulin sensitivity and glucose tolerance. The waking salivary cortisol of the subjects steadily and significantly decreased ( p = 0.026) in the RiaGev group in contrast to the placebo."}],"candidate_sources":[]},{"claim_id":"claim_25","claim":"Roy 2026 [bundle:9] (A combination of ketones and NAD + precursor preserves white matter integrity in mild cognitive impairment; representative statistic P < 0.001; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1).","citation_support":[{"source_id":"source_9","study":"A combination of ketones and NAD + precursor preserves white matter integrity in mild cognitive impairment","doi":"10.1002/trc2.70278","url":"https://doi.org/10.1002/trc2.70278","support_kind":"bundle_reference","cited_as":"Roy 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"Total gray matter ketone uptake increased by 2.4‐fold ( p < 0.001) in the active group, with no change in gray matter glucose uptake in either group. In WM, ketone uptake increased in the active group by 3.1–3.6‐fold across all seven tracts of interest ( p < 0.001). In the placebo group, myelin density declined by up to 10% in specific regions of the fornix ( p = 0.027), with no change in the active group.","excerpt":"Total gray matter ketone uptake increased by 2.4‐fold ( p < 0.001) in the active group, with no change in gray matter glucose uptake in either group. In WM, ketone uptake increased in the active group by 3.1–3.6‐fold across all seven tracts of interest ( p < 0.001). In the placebo group, myelin density declined by up to 10% in specific regions of the fornix ( p = 0.027), with no change in the active group."}],"candidate_sources":[]},{"claim_id":"claim_26","claim":"Yu 2025 [bundle:4] (Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized; representative non-significant statistic p = 0.088; not treated as positive or negative directional support unless source direction is coded; outcome=Muscle Function; direction=negative; directness=direct; tier=A1).","citation_support":[{"source_id":"source_4","study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","support_kind":"bundle_reference","cited_as":"Yu 2025","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115)."}],"candidate_sources":[]},{"claim_id":"claim_27","claim":"Connell 2021 [bundle:5] (NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial; representative non-significant statistic P = 0.716; not treated as positive or negative directional support unless source direction is coded; outcome=Muscle Function; direction=null; directness=direct; tier=A1).","citation_support":[{"source_id":"source_5","study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","support_kind":"bundle_reference","cited_as":"Connell 2021","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR"}],"candidate_sources":[]},{"claim_id":"claim_28","claim":"Simic 2020 [bundle:3] (Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a; representative statistic p = 0.002; source-level statistic reported; outcome=Safety and Comorbidity; direction=unclear; directness=direct; tier=A1).","citation_support":[{"source_id":"source_3","study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","doi":"10.1186/s12882-020-02006-1","url":"https://doi.org/10.1186/s12882-020-02006-1","support_kind":"bundle_reference","cited_as":"Simic 2020","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was","excerpt":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD + response to treatment. Considering all Steps together, NRPT treatment increased NAD + levels by 37% at 48 h compared to 0 h ( p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. NRPT increases whole blood NAD + levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. NCT03176628 , date of registration June 5th, 2017. Keywords: Acute kidney injury, NAD + , Nicotinamide riboside, Pterostilbene, Safety study Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. AKI is most commonly diagnosed in patients following major invasive surgical procedures, in the setting of sepsis, or following administration of certain drugs or contrast dyes, particularly in patients with underlying hypertension, diabetes, or chronic kidney disease [ 1 ]. There is currently no specific treatment for AKI. Supportive measures include dialysis for patients with severe AKI, and mortality in this subset of patients exceeds 50% [ 2 ]. Thus, new preventive and treatment approaches are urgently needed. Nicotinamide adenine dinucleotide (NAD + ) is a key cellular factor linked to metabolism and longevity [ 3 ]. It is a required co-factor of SIRT1, a nuclear deacetylase that modulates chromatin structure, gene expression, extends lifespan in lower organisms, and improves many aging related diseases [ 4 , 5 ]. Experimental AKI in mice rapidly leads to the reduction of NAD + levels in the kidney that results from a combination of decreased NAD + biosynthesis and increased NAD + consumption [ 6 ]. NAD + augmentation by niacinamide has been shown to prevent various etiologies of experimental AKI in mice, and an initial pilot study has demonstrated the safety of niacinamide in patients undergoing cardiac surgery [ 7 ]. Further, mice deficient in SIRT1 are more susceptible to AKI and overexpression of SIRT1 protects from AKI [ 8 ]. These studies outline NAD + and SIRT1 modulation as a potential therapeutic approach in AKI [ 9 ]. Nicotinamide riboside with pterostilbene (NRPT) is a combination of nicotinamide riboside (NR), a form of vitamin B3, and pterostilbene (PT), a polyphenol found in blueberries [ 10 ]. NR is in wide use as an NAD + precursor, with distinct and superior pharmacokinetics to other NAD + intermediates in vitamin B metabolism such as nicotinic acid and niacinamide [ 11 ]. Through its effect on NAD + levels and SIRT1 activity, NR has been shown to have metabolic benefits and efficacy in a variety of disease models and to modestly increase lifespan in aged mice [ 12 ]. PT is a natural equivalent of the polyphenol resveratrol, an effective SIRT1 activator [ 13 ], that has greater bioavailability [ 14 ]. Therefore, the combination of NR and PT is predicted to have synergistic effect on metabolism, with NR augmenting NAD + levels and PT additionally activating SIRT1 [ 10 ]. NR supplementation alone has been studied in humans with cardiovascular [ 15 ], systemic metabolic [ 16 ], exercise [ 17 ], and muscle aging related end-points [ 18 ]. Further, NRPT has been evaluated in healthy elderly adults (age 60 to 80 years) and was shown to safely increase the blood concentration of NAD + in a dose-dependent manner by 40–90% [ 10 ]. To date, NR or NRPT have not been tested in patients with kidney disease. Thus, we sought to test the effect of escalating doses of NRPT on blood NAD+ levels and safety parameters in patients hospitalized with AKI, with the ultimate goal to test NRPT for the treatment of AKI. The incidence of AKI in hospitalized patients is about 1.6% with mortality rate of up to 35% [ 19 ]. AKI is associated with higher rates of death, subsequent hospitalization for stroke, heart failure, or myocardial infarction [ 20 ] and it accelerates the progression of CKD [ 21 ]. The management of patients with AKI is supportive, with renal replacement therapy indicated in patients with severe kidney injury. Currently, there are no specific therapeutics for the prevention and or management of AKI. Most studies in patients with AKI have focused on AKI after cardiac surgery, investigating renal perfusion, including studies investigating dopamine and neseritide, fenoldopam, aspirin or clonidine, buffered crystalloid, and remote ischemic preconditioning (reviewed in [ 22 ]), all to no avail. Trials examining the use of sodium bicarbonate or N-acetylcysteine in contrast induced nephropathy prevention have been inconclusive [ 23 ]. Because this prior focus on hemodynamics and perfusion has been unsuccessful, there has been increasing interest in augmenting kidney metabolic health by increasing NAD + levels and action as a novel therapeutic approach in AKI [ 7 , 9 ]. To our knowledge this is the first study describing whole blood NAD + levels in human AKI, with or without intervention. Across all treated individuals, NRPT treatment resulted in a significant increase in whole blood NAD + at 48 h. In placebo treated individuals, AKI resulted in a 50% decrease in whole blood NAD + levels at this time point. NRPT at all four tested doses was safe and well tolerated. These results motivate additional studies of NRPT as a potential therapeutic option in AKI. Our prespecified secondary endpoint was to determine the dose of NRPT that safely achieves at least a 50% increase (and up to a 100% increase) from baseline in cellular NAD + levels. The only dose of NRPT that resulted in a statistically significant increase in whole blood NAD + levels at 48 h as compared to 0 h was 500 mg/100 mg in Step 2, yielding a 47% increase. The Step 3 dose resulted in a 67% increase in whole blood NAD + levels that was not statistically significant. Thus in retrospect, the initial goal of a 50 to 100% increase in NAD + levels was likely set too high, in large part because it was based on studies in healthy volunteers [ 10 , 11 ] without accounting for such a profound decrease in whole blood NAD + levels with kidney injury (50% decrease after 2 days of AKI). NR alone was previously tested at similar doses (100, 300 and 1000 mg) in a study of 12 healthy volunteers, resulting in a significant increase in peripheral blood mononuclear cell NAD + levels after 24 h (all NR doses combined) and no effect during earlier time points (1, 2, 4 and 8 h) [ 11 ]. The relative increase in NAD + at 24 h vs 0 h was 46% for both 300 mg and 1000 mg of NR and only 12% for 100 mg of NR. NAD + was not measured beyond 24 h in this study [ 11 ]. We now show, in patients with AKI, a comparable increase in NAD + levels (40% at 48 h vs 0 h in all Steps combined), but with delayed effect to 48 h. This could represent slower incline in cellular NAD + in patients with AKI or the effect of PT. We have previously tested the combination of NR and PT (NRPT 250 mg/50 mg and 500 mg/100 mg) in 120 elderly healthy volunteers, with the focus on NAD + levels at later time points, namely after 30 and 60 days of treatment [ 10 ]. After 30 days of treatment, whole blood NAD + levels in the healthy elderly population increased by 40% in NRPT 250/50 mg and 90% in NRPT 500/100 mg treatment groups and the effect was sustained until 60 days [ 10 ]. In our study, NRPT at the same doses in an AKI population increased whole blood NAD + levels by 23 and 47% respectively at 48 h."}],"candidate_sources":[]},{"claim_id":"claim_29","claim":"Thesis:** Across 17 curated reference papers, the evidence base for NAD+ shows a context-dependent profile. Negative signals appear in: muscle function, cardiometabolic. Null findings dominate: Contextual Adjacent Evidence, muscle function. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The NAD+ broad aging-related case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established. This position is bounded by the included sources and does not imply clinical efficacy beyond the evidence profile.","citation_support":[],"candidate_sources":[{"study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","year":2025,"doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Wu 2025","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial","year":2025,"doi":"10.1002/lary.70173","url":"https://doi.org/10.1002/lary.70173","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Gao 2025","evidence_span":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p","excerpt":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p = 0.028). Tinnitus and aural fullness improved more in the NAD+ group, especially after 3 months.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","year":2020,"doi":"10.1186/s12882-020-02006-1","url":"https://doi.org/10.1186/s12882-020-02006-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Simic 2020","evidence_span":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was","excerpt":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD + response to treatment. Considering all Steps together, NRPT treatment increased NAD + levels by 37% at 48 h compared to 0 h ( p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. NRPT increases whole blood NAD + levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. NCT03176628 , date of registration June 5th, 2017. Keywords: Acute kidney injury, NAD + , Nicotinamide riboside, Pterostilbene, Safety study Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. AKI is most commonly diagnosed in patients following major invasive surgical procedures, in the setting of sepsis, or following administration of certain drugs or contrast dyes, particularly in patients with underlying hypertension, diabetes, or chronic kidney disease [ 1 ]. There is currently no specific treatment for AKI. Supportive measures include dialysis for patients with severe AKI, and mortality in this subset of patients exceeds 50% [ 2 ]. Thus, new preventive and treatment approaches are urgently needed. Nicotinamide adenine dinucleotide (NAD + ) is a key cellular factor linked to metabolism and longevity [ 3 ]. It is a required co-factor of SIRT1, a nuclear deacetylase that modulates chromatin structure, gene expression, extends lifespan in lower organisms, and improves many aging related diseases [ 4 , 5 ]. Experimental AKI in mice rapidly leads to the reduction of NAD + levels in the kidney that results from a combination of decreased NAD + biosynthesis and increased NAD + consumption [ 6 ]. NAD + augmentation by niacinamide has been shown to prevent various etiologies of experimental AKI in mice, and an initial pilot study has demonstrated the safety of niacinamide in patients undergoing cardiac surgery [ 7 ]. Further, mice deficient in SIRT1 are more susceptible to AKI and overexpression of SIRT1 protects from AKI [ 8 ]. These studies outline NAD + and SIRT1 modulation as a potential therapeutic approach in AKI [ 9 ]. Nicotinamide riboside with pterostilbene (NRPT) is a combination of nicotinamide riboside (NR), a form of vitamin B3, and pterostilbene (PT), a polyphenol found in blueberries [ 10 ]. NR is in wide use as an NAD + precursor, with distinct and superior pharmacokinetics to other NAD + intermediates in vitamin B metabolism such as nicotinic acid and niacinamide [ 11 ]. Through its effect on NAD + levels and SIRT1 activity, NR has been shown to have metabolic benefits and efficacy in a variety of disease models and to modestly increase lifespan in aged mice [ 12 ]. PT is a natural equivalent of the polyphenol resveratrol, an effective SIRT1 activator [ 13 ], that has greater bioavailability [ 14 ]. Therefore, the combination of NR and PT is predicted to have synergistic effect on metabolism, with NR augmenting NAD + levels and PT additionally activating SIRT1 [ 10 ]. NR supplementation alone has been studied in humans with cardiovascular [ 15 ], systemic metabolic [ 16 ], exercise [ 17 ], and muscle aging related end-points [ 18 ]. Further, NRPT has been evaluated in healthy elderly adults (age 60 to 80 years) and was shown to safely increase the blood concentration of NAD + in a dose-dependent manner by 40–90% [ 10 ]. To date, NR or NRPT have not been tested in patients with kidney disease. Thus, we sought to test the effect of escalating doses of NRPT on blood NAD+ levels and safety parameters in patients hospitalized with AKI, with the ultimate goal to test NRPT for the treatment of AKI. The incidence of AKI in hospitalized patients is about 1.6% with mortality rate of up to 35% [ 19 ]. AKI is associated with higher rates of death, subsequent hospitalization for stroke, heart failure, or myocardial infarction [ 20 ] and it accelerates the progression of CKD [ 21 ]. The management of patients with AKI is supportive, with renal replacement therapy indicated in patients with severe kidney injury. Currently, there are no specific therapeutics for the prevention and or management of AKI. Most studies in patients with AKI have focused on AKI after cardiac surgery, investigating renal perfusion, including studies investigating dopamine and neseritide, fenoldopam, aspirin or clonidine, buffered crystalloid, and remote ischemic preconditioning (reviewed in [ 22 ]), all to no avail. Trials examining the use of sodium bicarbonate or N-acetylcysteine in contrast induced nephropathy prevention have been inconclusive [ 23 ]. Because this prior focus on hemodynamics and perfusion has been unsuccessful, there has been increasing interest in augmenting kidney metabolic health by increasing NAD + levels and action as a novel therapeutic approach in AKI [ 7 , 9 ]. To our knowledge this is the first study describing whole blood NAD + levels in human AKI, with or without intervention. Across all treated individuals, NRPT treatment resulted in a significant increase in whole blood NAD + at 48 h. In placebo treated individuals, AKI resulted in a 50% decrease in whole blood NAD + levels at this time point. NRPT at all four tested doses was safe and well tolerated. These results motivate additional studies of NRPT as a potential therapeutic option in AKI. Our prespecified secondary endpoint was to determine the dose of NRPT that safely achieves at least a 50% increase (and up to a 100% increase) from baseline in cellular NAD + levels. The only dose of NRPT that resulted in a statistically significant increase in whole blood NAD + levels at 48 h as compared to 0 h was 500 mg/100 mg in Step 2, yielding a 47% increase. The Step 3 dose resulted in a 67% increase in whole blood NAD + levels that was not statistically significant. Thus in retrospect, the initial goal of a 50 to 100% increase in NAD + levels was likely set too high, in large part because it was based on studies in healthy volunteers [ 10 , 11 ] without accounting for such a profound decrease in whole blood NAD + levels with kidney injury (50% decrease after 2 days of AKI). NR alone was previously tested at similar doses (100, 300 and 1000 mg) in a study of 12 healthy volunteers, resulting in a significant increase in peripheral blood mononuclear cell NAD + levels after 24 h (all NR doses combined) and no effect during earlier time points (1, 2, 4 and 8 h) [ 11 ]. The relative increase in NAD + at 24 h vs 0 h was 46% for both 300 mg and 1000 mg of NR and only 12% for 100 mg of NR. NAD + was not measured beyond 24 h in this study [ 11 ]. We now show, in patients with AKI, a comparable increase in NAD + levels (40% at 48 h vs 0 h in all Steps combined), but with delayed effect to 48 h. This could represent slower incline in cellular NAD + in patients with AKI or the effect of PT. We have previously tested the combination of NR and PT (NRPT 250 mg/50 mg and 500 mg/100 mg) in 120 elderly healthy volunteers, with the focus on NAD + levels at later time points, namely after 30 and 60 days of treatment [ 10 ]. After 30 days of treatment, whole blood NAD + levels in the healthy elderly population increased by 40% in NRPT 250/50 mg and 90% in NRPT 500/100 mg treatment groups and the effect was sustained until 60 days [ 10 ]. In our study, NRPT at the same doses in an AKI population increased whole blood NAD + levels by 23 and 47% respectively at 48 h.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","year":2025,"doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Yu 2025","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115).","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","year":2021,"doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Connell 2021","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_30","claim":"Threat 1: The most direct cardiovascular evidence in the corpus yields null or marginal results, undermining the mechanistic narrative. This pattern suggests that NAD+ may produce short-term echocardiographic signals that fail to consolidate into durable functional benefit. Pei 2024 [bundle:11], examining older heart failure patients receiving intravenous NAD+ for seven days, reported improvement rates in NT-proBNP levels and LVEF values that were better than the saline group, although not statistically significant [Pei 2024] [bundle:11] [exact source: https://doi.org/10.31083/j.rcm2508297]. The evidence appears consistent with a pattern where NAD+ precursors generate preliminary cardiac biomarker improvements that remain qualified by small sample sizes and brief follow-up durations, making it uncertain whether these signals would survive adequately powered confirmatory trials.","citation_support":[{"source_id":"source_11","study":"Effects of Nicotinamide Adenine Dinucleotide on Older Patients with Heart Failure","doi":"10.31083/j.rcm2508297","url":"https://doi.org/10.31083/j.rcm2508297","support_kind":"bundle_reference","cited_as":"Pei 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"direct","evidence_span":"Based on using conventional drugs to treat HF, patients (n = 60) were randomized 1:1 to saline and 50 mg NAD + with 50 mL of normal saline for 7 days. The baseline characteristics of patients before and after treatment and cardiac function (N-terminal pro B-type natriuretic peptide (NT-proBNP) level and left ventricular ejection fraction (LVEF) value) were analyzed. Serological analysis (sirtuin-1 (SIRT1), sirtuin-3 (SIRT3), sirtuin-6 (SIRT6), reactive oxygen species (ROS), and endothelin) was also performed. Among the 60 patients with HF who were treated with NAD + for 7 days, the","excerpt":"Based on using conventional drugs to treat HF, patients (n = 60) were randomized 1:1 to saline and 50 mg NAD + with 50 mL of normal saline for 7 days. The baseline characteristics of patients before and after treatment and cardiac function (N-terminal pro B-type natriuretic peptide (NT-proBNP) level and left ventricular ejection fraction (LVEF) value) were analyzed. Serological analysis (sirtuin-1 (SIRT1), sirtuin-3 (SIRT3), sirtuin-6 (SIRT6), reactive oxygen species (ROS), and endothelin) was also performed. Among the 60 patients with HF who were treated with NAD + for 7 days, the improvement rate in NT-proBNP levels and LVEF values was better than in the saline group, although not statistically significant. These patients were more likely to benefit from NAD + because of higher levels of anti-oxidative stress (SIRT1, SIRT3, SIRT6, and ROS) and anti-endothelial injury (endothelin) than those in the saline control group. According to the results of this study, it is believed that 7 days of NAD + injections has a positive effect on improving cardiac function, oxidative stress, and endothelial injury in patients with HF compared with the saline control. Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ ) ChiCTR2300074326; retrospectively registered on 3 August 2023. Keywords: heart failure, NAD + , clinical study, adjuvant therapy Heart failure (HF) poses a serious threat to human health and is characterized by high morbidity, high mortality, a high rehospitalization rate, and many high-risk groups. The American Heart Association/American College of Cardiology guidelines define HF as “a complex clinical syndrome caused by any structural or functional heart disease that affects the ability of the ventricles to fill and shoot blood” [ 1 ]. Benjamin et al . [ 2 ] reported that patients hospitalized for HF are at an increased risk of HF rehospitalization and cardiovascular death. One in eight deaths is due to HF, and the mortality rate within 5 years of diagnosis is as high as 50%, exceeding that of some malignancies [ 2 ]. Despite the increased number of drugs used to treat HF, the fatality rate remains high. The 2021 European Society of Cardiology guidelines recommend a combination of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin-receptor neprilysin inhibitor, β -blockers, and aldosterone receptor antagonists (MRAs) as the primary treatment for chronic HF [ 3 ]. Both the previous “golden triangle” ( β -blocker, ACEI/angiotensin II receptor blocker [ARB], and MRA) and the current “five golden flowers” ( β -blocker, ACEI/ARB, MRA, and sodium-dependent glucose transporter 2 inhibitors) have limitations in clinical treatment [ 4 , 5 , 6 ]. Current drug therapy still cannot meet the needs of HF management, making it necessary to develop new treatment ideas and explore new treatment strategies. Nicotinamide adenine dinucleotide (NAD + ) is an important cofactor and a key metabolic enzyme substrate involved in redox reactions in the mitochondria, which is greatly significant in maintaining the balance of NAD + in vivo for normal human metabolism [ 7 ]. Several studies have shown that NAD + can inhibit inflammation and oxidative stress injury in endothelial cells, reduce apoptosis in microvascular endothelial cells, promote microangiogenesis, and improve microvascular injury caused by coronary microcirculation and myocardial ischemia-reperfusion [ 8 ]. Studies have also shown that the NAD + concentration in the blood of patients with HF is significantly lower than in healthy people, and with an increase in age, NAD + also has a trend of gradually decreasing [ 7 , 9 ]. Therefore, stabilizing intracellular NAD + levels through exogenous NAD + supplementation is expected to be a therapeutic strategy for improving cardiac bioenergetics and function. HF is the leading cause of hospitalization among older populations worldwide, with a high mortality rate and impact on the quality of life of patients [ 10 , 11 ]. With the development of medical technology, various drugs have emerged to treat HF. However, the effectiveness of these drugs remains unsatisfactory. HF remains an intractable disease, with an increased burden of hospitalization and a continuous loss of health care expenditure [ 12 ]. Therefore, it is necessary to identify alternative and complementary treatment options. Thus, we sought to evaluate whether NAD + therapy has some clinical efficacy in patients with HF. NAD + is widely present in the mitochondria of myocardial tissue, and NAD + activates the deacetylation activity of sirtuins, regulates the activity of numerous aging-related transcription factors, and intervenes in aging and aging-related diseases [ 9 , 13 , 14 ]. Several studies have shown that NAD + has beneficial effects on cardiovascular diseases by regulating metabolism, maintaining redox homeostasis, and modulating immune responses [ 15 , 16 , 17 ]. Studies have found that NAD + levels are significantly reduced in patients with HF [ 18 , 19 ]. In a rat model of myocardial infarction, compared with the LCZ696-positive drug control group, using NAD + improved some cardiac function and hemodynamic indexes and could further increase the left ventricular stroke output and systolic and diastolic blood pressure [ 20 ]. In the present clinical trial, we tested whether using exogenous NAD + supplementation as a new adjuvant treatment for HF is possible. NT-proBNP and LVEF are the most widely used laboratory indices for evaluating HF severity and prognosis. In our clinical trial, NT-proBNP levels improved in both groups, possibly because patients in both groups were rigorously treated with anti-HF drugs. However, the improvement was more obvious in the NAD + group than in the saline control group, which better reflects that the therapeutic effect of NAD + in patients with HF is independent of conventional medication for HF. Although the NT-proBNP level in the NAD + group improved from baseline, no statistically significant difference was found over time. This finding may be due to the large dispersion of the data, short treatment course, and small sample size; similarly, due to short-term drug use, changes in the structure and function of the heart cannot be obvious over a short time. Moreover, the measurement of LVEF is subjective to a certain extent and is related to the experience of the tester. LVEF in the NAD + group was improved, with no statistical difference between the groups. Studies have found that women may have lower NAD + concentrations and benefit most from improved heart function [ 21 , 22 ]. In our study, there was no statistical difference in gender between the two groups of patients, and whether women can benefit more from NAD + treatment will be our major direction in the future. Oxidative stress plays an important role in HF occurrence and progression [ 23 ]. The sirtuin family is also linked to several antioxidant and oxidative stress-related processes and functions [ 24 ]. Sirtuins are a family of seven enzymes (sirtuin1–7) involved in regulating many metabolic processes [ 25 ]. Sirtuin agonists are more convincing than existing deacetylase inhibitors for the treatment of cardiovascular diseases in terms of safety and efficacy and may have clinical value for treating multiple types of cardiovascular diseases [ 26 ]. Increasing the NAD + level in vivo can activate sirtuins, which can significantly inhibit myocardial hyperacetylation and improve myocardial mitochondrial function [ 27 ]. Clemency et al . [ 28 ] found that sodium-glucose cotransporter 2 (SGL-2) inhibitor could inhibit oxidative stress by increasing the expression of SIRT1 and SIRT3 and decreasing the expression of SIRT6, thereby alleviating myocardial injury. In our clinical trial, the SIRT1, SIRT3, and SIRT6 levels increased at the 2-week follow-up after medication, but over time, the concentration of exogenous supplemental NAD + gradually decreased in vivo and showed a trend of gradual decrease in the last two follow-up visits, which is also consistent with the metabolic process of intravenous drug use in the body. Furthermore, there was an interaction between SIRT1 in the saline control group and the NAD + group, which confirmed that NAD + plays a critical role in anti-oxidative stress. We observed that ROS levels increased in the NAD + group at the 2-week follow-up visit, possibly due to the negative feedback reaction of inflammation caused by the strong antioxidant effect in the short term. However, those levels improved at later visits. Increased levels of ET, the most potent vasoconstrictor, are produced by the pro-peptide precursor, large ET, through ET convertase [ 29 ]. ET in the peripheral blood of patients with HF can predict poor prognosis [ 30 , 31 , 32 ]. In this clinical trial, there were significant differences in ET levels between the saline control and NAD + groups, which confirmed that NAD + plays a more critical role in anti-endothelial injury. Although there was no difference in the incidence of composite endpoint events (including all-cause death and readmission due to HF) during the 1-year follow-up period in this study, there was still a significant difference in mortality between the two groups. The survival rate of NAD + was higher, and most patients who died were in the saline control group, usually 2–4 months after treatment. These results suggest that the use of NAD + may delay the progression of HF and reduce short-term mortality. The reason why no statistical difference was found in the various clinical endpoints in this study may be related to the small number of study cases, the short duration of NAD + administration, and the short follow-up time. Nevertheless, this study has expanded our ideas for exploring new treatments for patients with HF and confirmed their therapeutic effect on patients with HF based on molecular biology and echocardiography evaluation indicators. We also expect this study’s results to guide follow-up national multicenter, large-sample, prospective, randomized, double-blind controlled studies. We further confirmed the therapeutic effects of NAD + in the HF population. According to the product instructions, NAD + occasionally has side effects such as dry mouth, nausea, dizziness, and palpitations. However, in this clinical trial, patients had no obvious complaints after 7 days of intravenously administering NAD + , but the long-term effect or safety of treatment still needs to be observed over a longer study period. In addition, the follow-up of participants after completing this clinical trial may be limited, making it difficult to assess long-term outcomes and treatment safety. Our study consisted of a small sample size from a single center, potentially limiting the generalizability of our findings to a broader population of HF patients. Future multicenter studies covering cohorts with different demographic and clinical characteristics would help validate our findings and enhance external validity. In addition, we did not perform cardiovascular magnetic resonance to assess patients with HF more comprehensively. We did not discuss the pharmacological background of HF patients further, and our future research direction will be to focus on their pharmacological background. Among patients with HF, those injected with NAD + for 7 days may benefit more from improved cardiac function, levels of anti-oxidative stress, and endothelial injury than those re"}],"candidate_sources":[]}]}},{"name":"claim_graph.json","media_type":"application/json","content":{"publication_id":"9be40a10-b14d-4e4a-afff-f058a818c80b","content_hash":"sha256:dd03997af210fe86bc2fc10eef98e240ef8ee22849d3350bb8e4568a5055ae15","nodes":[{"id":"9be40a10-b14d-4e4a-afff-f058a818c80b","type":"publication","title":"Adjacent Evidence Brief: NAD+ Cardiovascular Effects"},{"id":"claim_1","type":"claim","text":"Null findings have a specific role in this evidence model. They do not erase mechanistic plausibility, but they do narrow the set of claims that can be made about effect consistency, target population, and endpoint selection."},{"id":"claim_2","type":"claim","text":"For instance, while one trial reported a trend toward improved NYHA class in heart failure patients [Yu 2025] [bundle:4], other trials in different populations found null effects on functional endpoints, such as mitochondrial respiration and skeletal muscle function in older adults [Connell 2021] [bundle:5] and cognition in long-COVID patients [Wu 2025] [bundle:1] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.1093/jn/nxab193] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633]."},{"id":"claim_3","type":"claim","text":"Null findings have a specific role in this evidence model. They do not erase mechanistic plausibility, but they do narrow the set of claims that can be made about effect consistency, target population, and endpoint selection."},{"id":"claim_4","type":"claim","text":"For instance, while one trial reported a trend toward improved NYHA class in heart failure patients [Yu 2025] [bundle:4], other trials in different populations found null effects on functional endpoints, such as mitochondrial respiration and skeletal muscle function in older adults [Connell 2021] [bundle:5] and cognition in long-COVID patients [Wu 2025] [bundle:1] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.1093/jn/nxab193] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633]."},{"id":"claim_5","type":"claim","text":"The geroscience framework reframes the clinical challenge: rather than developing separate therapies for heart failure, atherosclerosis, and metabolic syndrome, one might target the shared biological substrate of aging itself. NAD+ precursors, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), represent a drug class that has moved rapidly from preclinical observation to human supplementation trials. The regulatory pathway for these compounds has been complex; they are often marketed as dietary supplements, which permits consumer access but limits the regulatory oversight and standardized dosing that characterize pharmaceutical development. Another trial demonstrated that a combination of nicotinamide and D-ribose (RiaGev) increased the NAD+ metabolome, with NADP+ rising by 27% compared to placebo after seven days of supplementation [Xue 2022] [bundle:7] [exact source: https://doi.org/10.3390/nu14112219]. These findings confirm that oral precursors can reliably raise circulating NAD+, but the critical question is whether this biochemical elevation translates into clinically meaningful cardiovascular protection."},{"id":"claim_6","type":"claim","text":"A review of the human RCT landscape reveals a striking heterogeneity in study populations, interventions, and endpoints, with very few trials directly assessing cardiovascular outcomes. The most direct cardiovascular evidence comes from a trial in patients with heart failure caused by ischemic cardiomyopathy, where intravenous NAD+ was compared to placebo. This study reported a statistically significant improvement in left ventricular ejection fraction (LVEF) within the NAD+ group at one month, but the between-group comparison for New York Heart Association (NYHA) class improvement showed only a trend (P = 0.088 at one month, P = 0.115 at six months) [Yu 2025] [bundle:4] [exact source: https://doi.org/10.1007/s40256-025-00764-7]. A separate trial in older adults with heart failure found that seven days of intravenous NAD+ injection improved NT-proBNP levels and LVEF values compared to saline, although the differences were not statistically significant [Pei 2024] [bundle:11] [exact source: https://doi.org/10.31083/j.rcm2508297]. Other trials have examined NAD+ precursors in populations with acute kidney injury [Simic 2020 [bundle:3], Pencina 2025 [bundle:12]], long-COVID [Wu 2025] [bundle:1], sudden sensorineural hearing loss [Gao 2025] [bundle:2], and mild cognitive impairment [Roy 2026] [bundle:9], where cardiovascular endpoints were not the primary focus [exact source: https://doi.org/10.1186/s12882-020-02006-1] [exact source: https://doi.org/10.1096/fba.2025-00014] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633] [exact source: https://doi.org/10.1002/lary.70173] [exact source: https://doi.org/10.1002/trc2.70278]. This fragmentation of the evidence base means that any synthesis of cardiovascular effects must draw indirect inferences from trials designed for other purposes."},{"id":"claim_7","type":"claim","text":"Several unresolved questions complicate the interpretation of the existing evidence. First, the mechanism by which elevated NAD+ might improve cardiac function remains poorly defined in humans; proposed pathways include enhanced mitochondrial bioenergetics, reduced oxidative stress, and improved endothelial function, but these are largely extrapolated from preclinical models. Second, the duration of supplementation in most trials is short—often weeks to a few months—raising the question of whether longer-term exposure is necessary for cardiovascular benefit or whether it introduces unforeseen risks. Third, dose-response relationships are unclear; trials have used a wide range of doses, from 250 mg/day of NMN [Katayoshi 2023] [bundle:10] to 1000 mg twice daily of NR [Airhart 2017] [bundle:15], and the optimal dose for cardiovascular protection is unknown [exact source: https://doi.org/10.1038/s41598-023-29787-3] [exact source: https://doi.org/10.1371/journal.pone.0186459]. Fourth, population specificity is a concern, as the most promising cardiovascular signals come from patients with established heart failure [Yu 2025 [bundle:4], Pei 2024 [bundle:11]], while trials in healthier populations have not demonstrated clear cardiovascular benefits [Martens 2018] [bundle:16] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.31083/j.rcm2508297] [exact source: https://doi.org/10.1038/s41467-018-03421-7]. Finally, the trade-off between potential benefits and safety in vulnerable populations, such as those with acute kidney injury, requires careful evaluation [Simic 2020 [bundle:3], Pencina 2025 [bundle:12]] [exact source: https://doi.org/10.1186/s12882-020-02006-1] [exact source: https://doi.org/10.1096/fba.2025-00014]."},{"id":"claim_8","type":"claim","text":"The current evidence base presents significant cross-outcome tensions that must be explicitly addressed. For instance, while one trial reported a trend toward improved NYHA class in heart failure patients [Yu 2025] [bundle:4], other trials in different populations found null effects on functional endpoints, such as mitochondrial respiration and skeletal muscle function in older adults [Connell 2021] [bundle:5] and cognition in long-COVID patients [Wu 2025] [bundle:1] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.1093/jn/nxab193] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633]. This synthesis will separate mechanistic evidence from clinical evidence, acknowledging that biochemical changes (for example, increased NAD+ levels) do not automatically confer clinical benefit. The structured evidence weighting will prioritize direct human RCT data with cardiovascular endpoints, while clearly delineating the indirect evidence from trials focused on other outcomes. The goal is to provide a transparent assessment of where the evidence is strong, where it is suggestive, and where significant gaps remain, particularly regarding the long-term cardiovascular effects of NAD+ precursor supplementation in diverse human populations."},{"id":"claim_9","type":"claim","text":"The evidence profile indicates that the case for NAD+ precursors as cardiovascular therapeutics is currently incomplete. Mechanistic plausibility is supported by the central role of NAD+ in cellular metabolism and the consistent ability of oral precursors to raise circulating levels [Airhart 2017 [bundle:15], Xue 2022 [bundle:7]] [exact source: https://doi.org/10.1371/journal.pone.0186459] [exact source: https://doi.org/10.3390/nu14112219]. However, the human RCT evidence is sparse and mixed. Direct cardiovascular trials are limited to small studies in heart failure populations with short follow-up and non-significant or trend-level between-group differences [Yu 2025 [bundle:4], Pei 2024 [bundle:11]] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.31083/j.rcm2508297]. The broader trial landscape includes studies in non-cardiovascular populations where cardiovascular endpoints were not assessed or were secondary [Wu 2025 [bundle:1], Gao 2025 [bundle:2], Roy 2026 [bundle:9]] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633] [exact source: https://doi.org/10.1002/lary.70173] [exact source: https://doi.org/10.1002/trc2.70278]. Furthermore, some trials in relevant populations, such as older adults, have failed to show functional benefits on muscle or mitochondrial endpoints [Connell 2021] [bundle:5] [exact source: https://doi.org/10.1093/jn/nxab193]. The boundary conditions for any potential benefit—including optimal dose, duration, patient selection, and the specific cardiovascular outcomes that might respond—remain to be established. This synthesis aims to map these boundaries by systematically evaluating the available evidence, highlighting both the promises and the significant uncertainties that currently define the field."},{"id":"claim_10","type":"claim","text":"Risk-of-bias honesty note: No populated per-source public appraisal ratings are reported in this artifact. Risk-of-bias language is therefore descriptive of source design and directness, not a claim that formal framework-specific scoring was completed."},{"id":"claim_11","type":"claim","text":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text."},{"id":"claim_12","type":"claim","text":"A source was coded as direct only when it tested the topic itself against a clinically proximate outcome in the relevant population. Human evidence with an adjacent exposure, population, or outcome was coded as indirect; syntheses and secondary reviews were coded as review-level evidence and were not counted as direct sources."},{"id":"claim_13","type":"claim","text":"Risk-of-bias framework assignment follows study design (risk-of-bias appraisal for RCTs, non-randomized-study appraisal for non-randomised studies, review-quality appraisal for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification."},{"id":"claim_14","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, muscle function, safety and comorbidity); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates."},{"id":"claim_15","type":"claim","text":"| Evidence domain | Corpus slice | Direction profile | Directness | Main limitation |"},{"id":"claim_16","type":"claim","text":"| NAD+ Cardiovascular Effects / Contextual Adjacent Evidence | n=7; claims=174 | positive=0, negative=0, null=1, mixed=0, unclear=6 (n=7) | 7 direct | limited corpus depth in this outcome class |"},{"id":"claim_17","type":"claim","text":"| NAD+ Cardiovascular Effects / Muscle Function | n=4; claims=100 | positive=0, negative=1, null=1, mixed=0, unclear=2 (n=4) | 4 direct | limited corpus depth in this outcome class |"},{"id":"claim_18","type":"claim","text":"| NAD+ Cardiovascular Effects / Animal/Preclinical Context | n=2; claims=27 | positive=0, negative=0, null=0, mixed=0, unclear=2 (n=2) | 2 mechanistic | limited corpus depth in this outcome class |"},{"id":"claim_19","type":"claim","text":"| NAD+ Cardiovascular Effects / Safety and Comorbidity | n=2; claims=52 | positive=0, negative=0, null=0, mixed=1, unclear=1 (n=2) | 2 direct | limited corpus depth in this outcome class |"},{"id":"claim_20","type":"claim","text":"| NAD+ Cardiovascular Effects / Cardiometabolic | n=1; claims=13 | positive=0, negative=1, null=0, mixed=0, unclear=0 (n=1) | 1 direct | single-source slice; hypothesis-generating |"},{"id":"claim_21","type":"claim","text":"| NAD+ Cardiovascular Effects / Dosing and Pharmacokinetics | n=1; claims=29 | positive=0, negative=0, null=0, mixed=0, unclear=1 (n=1) | 1 direct | single-source slice; hypothesis-generating |"},{"id":"claim_22","type":"claim","text":"Wu 2025 [bundle:1] (Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled; representative statistic P < 0.001; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=null; directness=direct; tier=A1)."},{"id":"claim_23","type":"claim","text":"Gao 2025 [bundle:2] (NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial; representative statistic P = 0.030; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1)."},{"id":"claim_24","type":"claim","text":"Xue 2022 [bundle:7] (A Combination of Nicotinamide and D-Ribose (RiaGev) Is Safe and Effective to Increase NAD + Metabolome in Healthy; representative statistic P = 0.033; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1)."},{"id":"claim_25","type":"claim","text":"Roy 2026 [bundle:9] (A combination of ketones and NAD + precursor preserves white matter integrity in mild cognitive impairment; representative statistic P < 0.001; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=unclear; directness=direct; tier=A1)."},{"id":"claim_26","type":"claim","text":"Yu 2025 [bundle:4] (Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized; representative non-significant statistic p = 0.088; not treated as positive or negative directional support unless source direction is coded; outcome=Muscle Function; direction=negative; directness=direct; tier=A1)."},{"id":"claim_27","type":"claim","text":"Connell 2021 [bundle:5] (NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial; representative non-significant statistic P = 0.716; not treated as positive or negative directional support unless source direction is coded; outcome=Muscle Function; direction=null; directness=direct; tier=A1)."},{"id":"claim_28","type":"claim","text":"Simic 2020 [bundle:3] (Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a; representative statistic p = 0.002; source-level statistic reported; outcome=Safety and Comorbidity; direction=unclear; directness=direct; tier=A1)."},{"id":"claim_29","type":"claim","text":"Thesis:** Across 17 curated reference papers, the evidence base for NAD+ shows a context-dependent profile. Negative signals appear in: muscle function, cardiometabolic. Null findings dominate: Contextual Adjacent Evidence, muscle function. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The NAD+ broad aging-related case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established. This position is bounded by the included sources and does not imply clinical efficacy beyond the evidence profile."},{"id":"claim_30","type":"claim","text":"Threat 1: The most direct cardiovascular evidence in the corpus yields null or marginal results, undermining the mechanistic narrative. This pattern suggests that NAD+ may produce short-term echocardiographic signals that fail to consolidate into durable functional benefit. Pei 2024 [bundle:11], examining older heart failure patients receiving intravenous NAD+ for seven days, reported improvement rates in NT-proBNP levels and LVEF values that were better than the saline group, although not statistically significant [Pei 2024] [bundle:11] [exact source: https://doi.org/10.31083/j.rcm2508297]. The evidence appears consistent with a pattern where NAD+ precursors generate preliminary cardiac biomarker improvements that remain qualified by small sample sizes and brief follow-up durations, making it uncertain whether these signals would survive adequately powered confirmatory trials."},{"id":"source_1","type":"source","study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","year":2025,"doi":"10.1016/j.eclinm.2025.103633","url":"https://doi.org/10.1016/j.eclinm.2025.103633","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Wu 2025","evidence_span":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019","excerpt":"In long-COVID, NR increased NAD+ within 5 weeks but did not significantly improve cognition, fatigue, sleep, or mood vs. PBO. Exploratory analyses suggested within-group benefits after 10 weeks of NR, supporting the need for larger trials. This work was supported by Niagen Bioscience, the MGH McCance Center for Brain Health, Lavine Brain Health Innovation Fund, MGH ECOR CDI Physician-Scientist Development Award, and the Alzheimer's Association (grant no. AARGD-23-114103). Keywords: PASC, SARS-CoV-2, Fatigue, Depression, Sleep, Nicotinamide adenine dinucleotide The coronavirus disease 2019 (COVID-19) pandemic has produced over 770 million reported cases worldwide, according to the World Health Organization (WHO). While most individuals recover from the acute phase of infection, it is estimated that at least 7% of survivors experience persistent and often debilitating symptoms lasting for months or even years post-infection, a condition referred to as Post-Acute Sequelae of COVID-19, Post-COVID-19 Condition, or long-COVID. 1 , 2 , 3 Long-COVID affects individuals across all age groups and severities of acute illness, with the highest proportion of diagnoses occurring in middle-aged and non-hospitalized patients who had mild to moderate acute illness. 3 , 4 It manifests as a multi-systemic condition, with neurological symptoms, such as cognitive difficulties (i.e., attention, executive functioning, and memory deficits), headaches, and sleep disruptions, among the most prominent and incapacitating. 4 , 5 , 6 Additional common symptoms include fatigue, shortness of breath, muscle aches, and psychiatric symptoms including depression and anxiety. 3 , 7 These persistent symptoms often result in substantial declines in quality of life and long-term disability, 8 underscoring the urgent need to identify treatment targets and develop effective interventions. Several pathophysiological mechanisms contribute to long-COVID, including immune dysregulation, characterized by elevated pro-inflammatory cytokines, alterations in T-cell populations, and autoantibody production, along with mitochondrial dysfunction, oxidative stress, and disruptions in energy metabolism. 9 , 10 , 11 One emerging target in this context is nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular metabolism, immune regulation, and inflammation control that is found in every cell of the human body. 3 , 12 As a key electron carrier in the mitochondrial respiratory chain, NAD+ regulates essential metabolic pathways, including glycolysis, the Krebs cycle, and fatty acid oxidation. 13 , 14 It also plays a vital role in DNA repair and cellular resilience by activating poly (ADP-ribose) polymerase (PARP) enzymes, which help maintain genomic stability and prevent excessive cell death. 13 SARS-CoV-2 infection has been shown to dysregulate NAD+-dependent pathways. 9 , 12 , 15 Specifically, the virus activates PARP family genes, increasing NAD+ consumption and depletion. 16 A study measuring NAD+ and its metabolites in hospitalized COVID-19 patients found significantly lower NAD+ levels compared to control groups, along with altered levels of NAD+ metabolites such as 1-methyl nicotinamide and nicotinamide. 17 Gene expression analyses further revealed disruptions in immune response, metabolism, apoptosis, redox balance, and mitochondrial function, some of which are present in long-COVID. 17 Given NAD+’s role in mitochondrial function and immune regulation, its sustained depletion could help explain the lingering metabolic and neurological symptoms observed in long-COVID. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), has been shown to effectively increase NAD+ levels and confer various health benefits. Preclinical studies indicate that NR reduces peripheral inflammation, cellular senescence and neuroinflammation and enhances oxidative metabolism, cognition, muscle function, motor coordination, and synaptic plasticity. 14 , 18 , 19 , 20 In humans, it has been shown to reduce circulating inflammatory cytokines in older adults. 21 , 22 A phase I clinical trial in Parkinson's disease patients demonstrated that NR supplementation enhanced the NAD+ metabolome and upregulated pathways associated with mitochondrial, lysosomal, and proteasomal function in blood cells and skeletal muscle. 23 Moreover, NR supplementation was associated with reduced inflammatory cytokine levels in both serum and cerebrospinal fluid. In addition, a small randomized, open-label, placebo-controlled phase II trial investigating the effects of a combination of metabolic cofactors (NR, l -serine, N-acetyl- l -cysteine, and l -carnitine tartrate) in people during acute COVID-19 found that this combination significantly reduced symptom duration. 24 However, since NR was administered alongside other cofactors, its independent effects remain unclear. Further research is needed to determine whether NR supplementation alone can improve long-COVID symptoms by boosting NAD+ levels. We conducted a double-blind, placebo (PBO)-controlled clinical trial with a PBO lead-in phase to evaluate the effects of NR on NAD+ levels in non-hospitalized individuals with long-COVID. We hypothesized that NR supplementation would enhance NAD+ levels, which in turn would be associated with improvements in cognitive function and a reduction in long-COVID symptoms. Participants were enrolled in the clinical trial between August 2021 and September 2023. A total of 72 potential participants were screened for eligibility. Of those, 61 were enrolled and randomized, and 58 completed baseline testing ( Fig. 1 ). Of the total that completed the baseline visit, 37 participants (64%) were assigned to follow the NR-NR sequence, and 21 participants (36%) followed the PBO-NR sequence ( Fig. 2 ). NR-NR and PBO-NR groups did not differ in baseline characteristics, except for sex assigned at birth, which was included as a covariate in all models ( Table 1 ). In the NR-NR group, 25 and 18 participants remained in the study at 10 and 20 weeks after baseline, corresponding to dropout rates of 32.4% and 51.4% from baseline, respectively. The most common reason for study withdrawal was COVID-19 reinfection, followed by AEs, changes in medications that could affect cognition, inability to comply with the study time commitment, relocation out of state, or loss to follow-up ( Supplementary Table S1 ). In the PBO-NR group, 18 participants remained at 10 and 20 weeks after baseline, with a dropout rate of 14.3% at each timepoint. Of the three people who withdrew from the study on this group, one was reinfected with COVID-19, one experienced an AE, and one had a change in a medication that could affect cognition ( Suplementary Table S1 ). Standard medical care continued if initiated and stable before enrollment. Several participants in the trial were taking medications known to have potential cognitive effects; however, a licensed clinician determined that these were unlikely to interfere with study outcomes, typically due to their low dosage and stable use. These medications included amphetamines (n = 7), an anticonvulsant (n = 1), tricyclic antidepressant (n = 1), and benzodiazepines (n = 5). All participants had been on a stable dose for at least 2 months prior to the screening visit and were required to maintain that dosage throughout the study. Consort diagram . Clinical trial design: Participants completed a screening visit to determine eligibility and were started on PBO. Baseline data were collected 2 weeks after the screening visit and participants were randomized 2:1 (NR:PBO). Those randomized to the NR group continued on NR for 20 weeks, while those in the PBO group continued on PBO for 10 more weeks and then took NR for 10 weeks. A follow-up call was made to assess for adverse events 2 weeks after the last visit. Demographic and clinical characteristics of the participants at baseline. Note : M, mean; SD, standard deviation; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; FSS, Fatigue Severity Scale; PSQI, Pittsburgh Sleep Quality Index. Sample sizes for NR-NR and PBO-NR are 28 and 19, respectively. Sample sizes for NR-NR and PBO-NR are 28 and 21, respectively. Sample sizes for NR-NR and PBO-NR are 21 and 16, respectively. The average compliance rates were 96.7 ± 4.8% and 96.6 ± 6.1% in the NR-NR and PBO-NR groups, respectively. There were no differences in the compliance rate between the two groups and across time (group ∗ time interaction term; p = 0.72). We then examined changes in NAD+ levels in each group. In the NR-NR group, NAD+ levels increased by an average of 3.1-fold after both 5 and 10 weeks of NR supplementation (95% CI: 2.7–3.5, p < 0.001). These levels remained elevated, with a 2.6-fold (95% CI: 1.9–3.3, p < 0.001) and 2.1-fold (95% CI: 1.6–2.7, p < 0.001) increase at 15 and 20 weeks of NR supplementation, respectively ( Fig. 3 ). In the PBO-NR group, NAD+ levels remained close to baseline (0.93- to 1.0-fold change, 95% CI: 0.5–1.4) during the initial 5 and 10 weeks of PBO. After switching to NR, levels rose to a 2.6-fold and 2.1-fold increase after 5 and 10 weeks of NR supplementation, respectively (95% CI: 1.9–3.3 and 1.6–2.7, p < 0.001; Fig."},{"id":"source_2","type":"source","study":"NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial","year":2025,"doi":"10.1002/lary.70173","url":"https://doi.org/10.1002/lary.70173","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Gao 2025","evidence_span":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p","excerpt":"The study with 38 participants (average age 41.74 years, 78.98% male, 42.11% right ear, average Pre‐PTA 76.88 dB HL) showed that the NAD+ group experienced significantly greater hearing improvement (40.21 dB HL) compared to the control group (23.06 dB HL, t = 2.722, p = 0.010). The effective rate was higher in the NAD+ group (94.44% vs. 60.00%, Z = −3.014, p = 0.003). Significant group × time interactions were noted in the NAD+ group ( F = 2.867, p = 0.030), with greater improvements from 7 days to 3 months post‐treatment. Recovery time was shorter in the NAD+ group (62.97 vs. 175.98 days, p = 0.028). Tinnitus and aural fullness improved more in the NAD+ group, especially after 3 months."},{"id":"source_3","type":"source","study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","year":2020,"doi":"10.1186/s12882-020-02006-1","url":"https://doi.org/10.1186/s12882-020-02006-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Simic 2020","evidence_span":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was","excerpt":"NRPT dosing was increased in each Step: Step 1250/50 mg, Step 2500/100 mg, Step 3750/150 mg and Step 41,000/200 mg. Blood NAD + levels were measured by liquid chromatography-mass spectrometry and safety was assessed by history, physical exam, and clinical laboratory testing. AKI resulted in a 50% reduction in whole blood NAD + levels at 48 h compared to 0 h in patients receiving placebo ( p = 0.05). There was a trend for increase in NAD + levels in all NRPT Steps individually at 48 h compared to 0 h, but only the change in Step 2 reached statistical significance (47%, p = 0.04), and there was considerable interindividual variability in the NAD + response to treatment. Considering all Steps together, NRPT treatment increased NAD + levels by 37% at 48 h compared to 0 h ( p = 0.002). All safety laboratory tests were unchanged by NRPT treatment, including creatinine, estimated glomerular filtration rate (eGFR), electrolytes, liver function tests, and blood counts. Three of 20 patients receiving NRPT reported minor gastrointestinal side effects. NRPT increases whole blood NAD + levels in hospitalized patients with AKI. In addition, NRPT up to a dose of 1000 mg/200 mg twice a day for 2 days is safe and well tolerated in these patients. Further studies to assess the potential therapeutic benefit of NRPT in AKI are warranted. NCT03176628 , date of registration June 5th, 2017. Keywords: Acute kidney injury, NAD + , Nicotinamide riboside, Pterostilbene, Safety study Acute kidney injury (AKI) is common, growing in incidence, and associated with significant morbidity and mortality. AKI is most commonly diagnosed in patients following major invasive surgical procedures, in the setting of sepsis, or following administration of certain drugs or contrast dyes, particularly in patients with underlying hypertension, diabetes, or chronic kidney disease [ 1 ]. There is currently no specific treatment for AKI. Supportive measures include dialysis for patients with severe AKI, and mortality in this subset of patients exceeds 50% [ 2 ]. Thus, new preventive and treatment approaches are urgently needed. Nicotinamide adenine dinucleotide (NAD + ) is a key cellular factor linked to metabolism and longevity [ 3 ]. It is a required co-factor of SIRT1, a nuclear deacetylase that modulates chromatin structure, gene expression, extends lifespan in lower organisms, and improves many aging related diseases [ 4 , 5 ]. Experimental AKI in mice rapidly leads to the reduction of NAD + levels in the kidney that results from a combination of decreased NAD + biosynthesis and increased NAD + consumption [ 6 ]. NAD + augmentation by niacinamide has been shown to prevent various etiologies of experimental AKI in mice, and an initial pilot study has demonstrated the safety of niacinamide in patients undergoing cardiac surgery [ 7 ]. Further, mice deficient in SIRT1 are more susceptible to AKI and overexpression of SIRT1 protects from AKI [ 8 ]. These studies outline NAD + and SIRT1 modulation as a potential therapeutic approach in AKI [ 9 ]. Nicotinamide riboside with pterostilbene (NRPT) is a combination of nicotinamide riboside (NR), a form of vitamin B3, and pterostilbene (PT), a polyphenol found in blueberries [ 10 ]. NR is in wide use as an NAD + precursor, with distinct and superior pharmacokinetics to other NAD + intermediates in vitamin B metabolism such as nicotinic acid and niacinamide [ 11 ]. Through its effect on NAD + levels and SIRT1 activity, NR has been shown to have metabolic benefits and efficacy in a variety of disease models and to modestly increase lifespan in aged mice [ 12 ]. PT is a natural equivalent of the polyphenol resveratrol, an effective SIRT1 activator [ 13 ], that has greater bioavailability [ 14 ]. Therefore, the combination of NR and PT is predicted to have synergistic effect on metabolism, with NR augmenting NAD + levels and PT additionally activating SIRT1 [ 10 ]. NR supplementation alone has been studied in humans with cardiovascular [ 15 ], systemic metabolic [ 16 ], exercise [ 17 ], and muscle aging related end-points [ 18 ]. Further, NRPT has been evaluated in healthy elderly adults (age 60 to 80 years) and was shown to safely increase the blood concentration of NAD + in a dose-dependent manner by 40–90% [ 10 ]. To date, NR or NRPT have not been tested in patients with kidney disease. Thus, we sought to test the effect of escalating doses of NRPT on blood NAD+ levels and safety parameters in patients hospitalized with AKI, with the ultimate goal to test NRPT for the treatment of AKI. The incidence of AKI in hospitalized patients is about 1.6% with mortality rate of up to 35% [ 19 ]. AKI is associated with higher rates of death, subsequent hospitalization for stroke, heart failure, or myocardial infarction [ 20 ] and it accelerates the progression of CKD [ 21 ]. The management of patients with AKI is supportive, with renal replacement therapy indicated in patients with severe kidney injury. Currently, there are no specific therapeutics for the prevention and or management of AKI. Most studies in patients with AKI have focused on AKI after cardiac surgery, investigating renal perfusion, including studies investigating dopamine and neseritide, fenoldopam, aspirin or clonidine, buffered crystalloid, and remote ischemic preconditioning (reviewed in [ 22 ]), all to no avail. Trials examining the use of sodium bicarbonate or N-acetylcysteine in contrast induced nephropathy prevention have been inconclusive [ 23 ]. Because this prior focus on hemodynamics and perfusion has been unsuccessful, there has been increasing interest in augmenting kidney metabolic health by increasing NAD + levels and action as a novel therapeutic approach in AKI [ 7 , 9 ]. To our knowledge this is the first study describing whole blood NAD + levels in human AKI, with or without intervention. Across all treated individuals, NRPT treatment resulted in a significant increase in whole blood NAD + at 48 h. In placebo treated individuals, AKI resulted in a 50% decrease in whole blood NAD + levels at this time point. NRPT at all four tested doses was safe and well tolerated. These results motivate additional studies of NRPT as a potential therapeutic option in AKI. Our prespecified secondary endpoint was to determine the dose of NRPT that safely achieves at least a 50% increase (and up to a 100% increase) from baseline in cellular NAD + levels. The only dose of NRPT that resulted in a statistically significant increase in whole blood NAD + levels at 48 h as compared to 0 h was 500 mg/100 mg in Step 2, yielding a 47% increase. The Step 3 dose resulted in a 67% increase in whole blood NAD + levels that was not statistically significant. Thus in retrospect, the initial goal of a 50 to 100% increase in NAD + levels was likely set too high, in large part because it was based on studies in healthy volunteers [ 10 , 11 ] without accounting for such a profound decrease in whole blood NAD + levels with kidney injury (50% decrease after 2 days of AKI). NR alone was previously tested at similar doses (100, 300 and 1000 mg) in a study of 12 healthy volunteers, resulting in a significant increase in peripheral blood mononuclear cell NAD + levels after 24 h (all NR doses combined) and no effect during earlier time points (1, 2, 4 and 8 h) [ 11 ]. The relative increase in NAD + at 24 h vs 0 h was 46% for both 300 mg and 1000 mg of NR and only 12% for 100 mg of NR. NAD + was not measured beyond 24 h in this study [ 11 ]. We now show, in patients with AKI, a comparable increase in NAD + levels (40% at 48 h vs 0 h in all Steps combined), but with delayed effect to 48 h. This could represent slower incline in cellular NAD + in patients with AKI or the effect of PT. We have previously tested the combination of NR and PT (NRPT 250 mg/50 mg and 500 mg/100 mg) in 120 elderly healthy volunteers, with the focus on NAD + levels at later time points, namely after 30 and 60 days of treatment [ 10 ]. After 30 days of treatment, whole blood NAD + levels in the healthy elderly population increased by 40% in NRPT 250/50 mg and 90% in NRPT 500/100 mg treatment groups and the effect was sustained until 60 days [ 10 ]. In our study, NRPT at the same doses in an AKI population increased whole blood NAD + levels by 23 and 47% respectively at 48 h."},{"id":"source_4","type":"source","study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","year":2025,"doi":"10.1007/s40256-025-00764-7","url":"https://doi.org/10.1007/s40256-025-00764-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Yu 2025","evidence_span":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ±","excerpt":"As illustrated in Table 2 , there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2 ). Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%) LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide As presented in Table 3 , there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2 ). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3 ). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups ( p > 0.05). Secondary outcomes and safety evaluation Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%) ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3 ). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month ( p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo ( p = 0.115)."},{"id":"source_5","type":"source","study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","year":2021,"doi":"10.1093/jn/nxab193","url":"https://doi.org/10.1093/jn/nxab193","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Connell 2021","evidence_span":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT,","excerpt":"Following supplementation, skeletal muscle NAD + concentrations [7.5 ± 1.9 compared with 7.9 ± 1.6 AU, respectively] in INT compared with CON conditions were not significantly different compared to the control condition, whereas skeletal muscle methyl-nicotinamide levels were significantly higher under NAD + -precursor supplementation [INT, 0.098 ± 0.063 compared with CON, 0.025 ± 0.014; P = 0.001], suggesting an increased NAD + metabolism. Conversely, neither ADP-stimulated [INT, 82.1 ± 19.0 compared with CON, 84.0 ± 19.2; P = 0.716] nor maximally uncoupled mitochondrial respiration [INT, 103.4 ± 30.7 compared with CON, 108.7 ± 33.4; P = 0.495] improved under NAD + -precursor supplementation, nor did net exercise efficiency during the submaximal cycling test [INT, 20.2 ± 2.77 compared with CON, 20.8 ± 2.88; P = 0.342]. Our findings are consistent with previous findings on NAD + efficacy in humans, and we show in community-dwelling, older adults with impaired physical function that NAD + -precursor supplementation through L-tryptophan, nicotinic acid, and nicotinamide does not improve mitochondrial or skeletal muscle function. This study was registered at clinicaltrials.gov as NCT03310034 . Keywords: NAD+-precursors, skeletal muscle, mitochondrial function, older adults, metabolism, muscle health Aging has been defined as the time-dependent decline of function ( 1 ), with 1 of the most striking features of the aging process being the progressive loss of skeletal muscle mass (sarcopenia) and, in turn, the decline of skeletal muscle physical function ( 2 ). The loss of skeletal muscle mass and function leads to mobility impairments, an increased risk of falls, physical frailty, and metabolic impairments ( 3 ). Hence, a compromised physical function increases the risk of dependency in activities of daily living and care needs. With society confronted with an ever-aging population, a large effort of research has focused on identifying strategies to promote healthy aging. Interestingly, the loss of skeletal muscle function is paralleled by an age-dependent decline in mitochondrial function ( 1 ), an established hallmark of aging that is considered to be a driving force behind skeletal muscle aging ( 4–6 ). Therefore, promoting the mitochondrial metabolism may be a promising strategy to negate the metabolic and functional disturbances seen in skeletal muscle during aging ( 7 ). One pathway that has received much attention in this context is the NAD + –sirtuin (SIRT) axis ( 8–11 ). The SIRT enzyme family is comprised of NAD + -dependent deacetylases involved in the regulation of mitochondrial metabolism ( 12 ), which act as sensors to the bioavailability of NAD + ( 13 ). The coenzyme NAD + and its reduced form NAD(H) are critical to the cellular redox potential and are the predominant electron donors in the electron transport chain. NAD + , however, is the rate-limiting substrate in SIRT activity, and NAD + bioavailability has been shown to decline with increasing age in mice ( 4 , 10 ) and humans ( 14 , 15 ). The human body derives NAD + from various dietary sources, as it can be synthesized de novo from the essential amino-acid L-tryptophan (L-Trp) or from niacin compounds such as nicotinic acid (NA) through the Preiss-Handler pathway, or salvaged from nicotinamide (NAM) and nicotinamide riboside (NR) ( 16 ). From a dietary perspective, NR is a trace element, whereas L-Trp, NA, and NAM are more abundantly available in our diets ( 17 ). Preclinical work in murine models of aging has demonstrated the efficacy of supplementing with NAD + precursors, such as NR and nicotinamide mononucleotide (NMN), to negate the effects of aging induced by declining NAD + levels ( 4 , 18 ), promote longevity ( 18 ), and improve energy metabolism, body weight, and mitochondrial oxidative metabolism ( 11 ). Following suit, several human intervention studies have focused on the use of the NAD + precursor NR to improve cardiovascular health in middle-aged to older adults ( 19 ), to combat metabolic dysfunction in middle-aged individuals with obesity ( 20 , 21 ), and to improve skeletal muscle metabolism in older adults ( 22 ). Although these studies provide some evidence on the efficacy of supplementation with NAD + precursors in older adults to increase NAD + levels in blood and skeletal muscle through NR supplementation, evidence stemming from studies involving older adults with compromised physical function and from studies focusing on skeletal muscle function are still lacking. Furthermore, other than through supplementation with high doses of NR or NA, there is only limited evidence discerning NAD + -precursor supplementation at lower doses. Dietary supplements bearing a greater resemblance to increased dietary intake may also have the potency to increase NAD + bioavailability in humans ( 23 , 24 ). Moreover, increasing NAD + synthesis from L-Trp by inhibiting the α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) enzyme also leads to activation of SIRT1 and its downstream health benefits ( 25 ). Here, we aim to elucidate the efficacy of NAD + -precursor supplementation through a novel combination of L-Trp, NA, and NAM on skeletal muscle mitochondrial function in community-dwelling, older adults with impaired physical function. Mitochondrial dysfunction is an established hallmark of aging and, together with declining NAD + levels, these factors are thought to drive the age-dependent decline in skeletal muscle physical function. Here, we hypothesized that supplementation with the NAD + precursors L-Trp, NA, and NAM, in a dose that could be achieved through increased dietary intake, would improve mitochondrial oxidative capacity in community-dwelling, older adults with impaired physical function. We tested this hypothesis by conducting a double-blind, randomized, controlled, cross-over trial with detailed metabolic phenotyping. We show that supplementing with L-Trp, NA, and NAM does elevate MeNAM concentrations in skeletal muscle tissue but, in discordance with our hypothesis, we found no improvement in the mitochondrial respiration capacity in older adults with an impaired physical function. In the current study, we did not observe an improvement in the mitochondrial respiratory capacity in skeletal muscle under NAD + -precursor supplementation compared to the control condition. We have previously shown that the NAD + precursor acipimox was able to improve the mitochondrial function in T2DM patients ( 44 ). However, the lack of an effect of NAD + -precursor supplementation in the current study is in accordance with similar recent observations with NR supplementation in individuals with obesity ( 45 , 46 ) and in older adults ( 22 ), and extends this observation to physically compromised older adults. Along the same lines, SPPB performance, energy expenditure, substrate utilization, and exercise efficiency were all unaffected by NAD + -precursor supplementation. These findings are in agreement with those of Martens et al. ( 19 ), who investigated the effects of NR supplementation in healthy, lean, middle-aged to older adults on parameters of physical function such as resting energy expenditure, maximum aerobic capacity, and body composition, and found no differences between NR and placebo. In accordance, Elhassan et al. ( 22 ) showed that 3 weeks of NR supplementation does not increase handgrip strength in older adults. In contrast to our previous finding that NR supplementation resulted in a minor but significant reduction in fat mass in middle-aged humans with obesity ( 45 ), we did not find any effect of NAD + -precursor supplementation on body composition in the current study. Also, the muscle volume was similar in both conditions. Interestingly, although no improvements in physical function were detected upon NAD + -precursor supplementation, perceived physical function was improved upon NAD + . Possibly, subtle changes in physical function did occur that were not detected by our outcome parameters. However, given the small number of volunteers in our study and the fact that this conclusion was based on 1 out of 9 domains of the RAND-36 survey, one should be cautious in interpreting this result. Future studies should determine both perceived compared with actual physical function in (NAD + ) supplementation studies. Blood pressure has also been reported to be susceptible to NAD + -precursor supplementation in humans ( 19 ). However, we did not observe changes in SBP, DBP, or MAP under NAD + -precursor supplementation. This is in agreement with our previous NR supplementation study in healthy humans with obesity, which revealed no improvements in SBP, DBP, or MAP when performing 36-hour blood pressure measurements ( 45 ). These data, however, conflict with previous findings from Martens et al. ( 19 ) showing improvements in SBP and DBP in healthy middle-aged to older adults following 6 weeks of NR"},{"id":"source_6","type":"source","study":"A randomized, controlled clinical trial demonstrates improved owner-assessed cognitive function in senior dogs receiving a senolytic and NAD+ precursor combination","year":2024,"doi":"10.1038/s41598-024-63031-w","url":"https://doi.org/10.1038/s41598-024-63031-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Simon 2024","evidence_span":"There was a significant difference in CCDR score across treatment groups from baseline to the primary endpoint (p = 0.02) with the largest decrease in the full dose group.","excerpt":"There was a significant difference in CCDR score across treatment groups from baseline to the primary endpoint (p = 0.02) with the largest decrease in the full dose group."},{"id":"source_7","type":"source","study":"A Combination of Nicotinamide and D-Ribose (RiaGev) Is Safe and Effective to Increase NAD + Metabolome in Healthy Middle-Aged Adults: A Randomized, Triple-Blind, Placebo-Controlled, Cross-Over Pilot Clinical Trial","year":2022,"doi":"10.3390/nu14112219","url":"https://doi.org/10.3390/nu14112219","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Xue 2022","evidence_span":"Supplementing with 1520 mg RiaGev twice daily for 7 days significantly increased the NAD + metabolome in blood, especially NADP + by 27% compared to the placebo group ( p = 0.033) and over the baseline ( p = 0.007). Increases in glutathione and high energy phosphates were also observed in the blood. Seven-day supplementation with RiaGev significantly ( p = 0.013) reduced overall blood glucose without significant changes in insulin secretion ( p = 0.796), suggesting an improved insulin sensitivity and glucose tolerance. The waking salivary cortisol of the subjects steadily and significantly","excerpt":"Supplementing with 1520 mg RiaGev twice daily for 7 days significantly increased the NAD + metabolome in blood, especially NADP + by 27% compared to the placebo group ( p = 0.033) and over the baseline ( p = 0.007). Increases in glutathione and high energy phosphates were also observed in the blood. Seven-day supplementation with RiaGev significantly ( p = 0.013) reduced overall blood glucose without significant changes in insulin secretion ( p = 0.796), suggesting an improved insulin sensitivity and glucose tolerance. The waking salivary cortisol of the subjects steadily and significantly decreased ( p = 0.026) in the RiaGev group in contrast to the placebo."},{"id":"source_8","type":"source","study":"Effect of C242T Polymorphism in the Gene Encoding the NAD(P)H Oxidase p22 phox Subunit and Aerobic Fitness Levels on Redox State Biomarkers and DNA Damage Responses to Exhaustive Exercise: A Randomized Trial","year":2020,"doi":"10.3390/ijerph17124215","url":"https://doi.org/10.3390/ijerph17124215","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Cho 2020","evidence_span":"Plasma lactate levels, SOD activities, and lymphocyte DNA damage markers (TD, TL, and TM) were significantly increased at IAE than that at IBE and significantly decreased at 30 MAE ( p < 0.05). All groups displayed increased plasma MDA levels at IAE rather than at IBE, with CC + MF being significantly higher than T + HF ( p < 0.05); only the CC + HF and T + HF groups exhibited a significant reduction at 30 MAE ( p < 0.05). Moreover, TL at IAE was significantly higher in the CC + MF group than in the T + HF group ( p < 0.05), and significantly higher in the CC + MF and CC + HF groups than in","excerpt":"Plasma lactate levels, SOD activities, and lymphocyte DNA damage markers (TD, TL, and TM) were significantly increased at IAE than that at IBE and significantly decreased at 30 MAE ( p < 0.05). All groups displayed increased plasma MDA levels at IAE rather than at IBE, with CC + MF being significantly higher than T + HF ( p < 0.05); only the CC + HF and T + HF groups exhibited a significant reduction at 30 MAE ( p < 0.05). Moreover, TL at IAE was significantly higher in the CC + MF group than in the T + HF group ( p < 0.05), and significantly higher in the CC + MF and CC + HF groups than in the T + HF group at 30 MAE ( p < 0.05). TM was significantly higher in the T + MF than in the T + HF group at IAE ( p < 0.05) and that of CC + MF was significantly higher than CC + HF and T + HF values at IAE and 30 MAE ( p < 0.05). These results suggest that single-bout exhaustive exercise could induce peripheral fatigue and the accumulation of temporary redox imbalance and oxidative DNA damage. Moreover, high aerobic fitness levels combined with the T allele may protect against exercise-induced redox imbalance and DNA damage. Keywords: CYBA gene, oxidative stress, maximum oxygen uptake Oxidative stress (OS) is induced when the body’s oxidant and antioxidant systems are unbalanced, as oxidation reactions predominate in the redox state [ 1 ]. Regular exercise training, which promotes antioxidant capacity, exerts antioxidant effects that can alleviate OS levels [ 2 ]. Alternatively, high-intensity exhaustive exercise requiring 10-fold oxygen supply and adenosine triphosphate (ATP) induces excessive reactive oxygen species (ROS) and free radical production, resulting in a rapid increase of the body’s OS-level [ 3 , 4 ]. Excessive ROS lowers exercise performance by inducing fatigue, owing to reduced calcium sensitivity during exercise, potentially resulting in inflammatory reactions and muscle damage [ 5 , 6 , 7 ]. Furthermore, it produces lipid peroxide through chain reactions with other fat components and can induce oxidative damage to cellular components, including lipids, proteins, and/or DNA [ 7 , 8 , 9 ]. Mitochondria, nicotinamide adenine dinucleotide phosphate oxidases (NOXs), phospholipase A2 (PLA2)-dependent processes, and xanthine oxidase are reportedly involved in ROS production [ 9 ]. Among these, NOXs constitute a principal source of cellular ROS and contribute to exercise-induced ROS production in skeletal muscles [ 9 , 10 ]. NOX is a multi-enzyme complex comprising the subunit proteins gp91 phox , p22 phox , p47 phox , p67 phox , and p40 phox [ 10 , 11 ]. Although p22 phox is expressed in non-phagocytic cells such as fibroblasts, endothelial cells and vascular smooth muscle cells, it is primarily expressed in phagocytic cells and is associated with superoxide production, which is decreased upon p22 phox suppression [ 12 , 13 ]. p22 phox is a ubiquitous protein and is encoded by the cytochrome blight chain ( CYBA ) gene, containing six exons, located on chromosome 16q24, for which over 177 polymorphisms have been reported [ 14 , 15 ]. Among these, the three genotypes of the C242T polymorphism (CC, CT, and TT) [ 16 , 17 ] are reportedly associated with differences in whole-body OS induction [ 18 , 19 , 20 ]. For example, Guzik et al. [ 18 ] examined NOX activity in 110 patients with coronary artery disease risk factors by obtaining samples from the saphenous vein. They reported that vascular NOX activity significantly decreases in subjects harboring the T allele and suggested that the T allele of C242T is associated with lower superoxide production [ 18 ]. Hashad et al. [ 19 ] examined the oxidized low-density lipoprotein (ox-LDL) levels, a blood OS marker, in the serum of 104 patients with acute myocardial infarction. They reported that patients with the CT genotype presented significantly lower ox-LDL levels than those harboring the CC genotype. Moreover, Meijles et al. [ 20 ] reported that the saphenous vein, harboring the TT allele, exhibited significantly lower superoxide generation upon high-glucose treatment. However, most studies have evaluated the effects of this polymorphism regarding the pathophysiological aspects of cardiovascular diseases; thus, the role of these variants in healthy subjects is unclear. High aerobic fitness potentially promotes endogenous antioxidant enzyme activation and is associated with high-intensity exercise-induced OS and DNA damage. Repka and Hayward [ 21 ] reported significant inverse correlations between peak oxygen uptake (VO 2 peak) and plasma 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels. Moreover, Djordjevic et al. [ 22 ] reported that superoxide dismutase (SOD) activity was significantly higher in athletes than in non-athletes. In addition, Bachi et al. [ 23 ] reported that athletes with high VO 2 max displayed significantly lower ox-LDL levels after a marathon. Moreno-Villanueva et al. [ 24 ] recently reported that untrained subjects (VO 2 max < 45 mL/kg/min) exhibited increased DNA strand breaks in lymphocytes after one-bout exercise compared to trained (VO 2 max > 55 mL/kg/min) subjects. Furthermore, the CYBA C242T polymorphism is reportedly associated with the exercise-induced OS, as CYBA requires the activation of oxidative enzymes in smooth muscle cells and is expressed in the coronary artery. However, studies investigating the effects of this polymorphism on OS levels regarding aerobic fitness status, which constitutes an important factor affecting body oxidant/antioxidant balance, are limited because most of them have been conducted under resting conditions with patients presenting pathologies including cardiovascular disease. Thus, in this study, we aimed to examine the exhaustive exercise-induced change in redox state biomarkers and oxidative DNA damage following the C242T polymorphism in the gene encoding p22 phox by evaluating healthy subjects at different aerobic fitness levels. NOXs constitute an important source of active oxygen along with mitochondria. Mammalian NOXs, including those of humans, comprise NOX1–5 and dual oxidases 1 and 2. These are composed of gp91 phox (cytochrome b558 heavy chain), primarily located within the cell membrane, and subdivided according to structural differences, including p22 phox , p47 phox , p67 phox , p40 phox , and the small GTP-binding protein Rac [ 30 , 31 ]. Among these, the gene encoding p22 phox is located on chromosome 16q24 and harbors the C242T polymorphism, through which histidine (His) is substituted with tyrosine (Tyr) at the 72nd codon, showing three associated genotypes (CC, CT, and TT) [ 16 , 17 ]. Several studies have reported differences in the distribution of alleles in the C242T polymorphism according to race (ethnicity). For example, Hashad et al. [ 19 ] analyzed the C242T polymorphism in an Egyptian population, reporting a 27.7% frequency for the CC genotype, 71.3% for the CT genotype, and 1% for the TT genotype. De Caterina et al. [ 32 ] reported frequencies of 36.4%, 47.7%, and 15.9%, respectively, among 1864 Italian individuals, indicating that the CT genotype displayed the highest distribution. Alternatively, Yamada et al. [ 33 ] analyzed the C242T polymorphism in 1074 Japanese subjects and reported that 816 (76.0%) harbored the CC, 242 (22.5%) harbored CT, and 16 (1.5%) reported TT genotypes. Similarly, an analysis of a Chinese population [ 34 ] revealed genotype frequencies of 87.2%, 12.2%, and 0.6%, respectively. Our results are consistent with those of other studies, including genotype frequencies at 81.8%, 16.4%, and 1.8%, for CC, CT, and TT genotypes, respectively, suggesting that the distribution of the CC genotype is highest among Asians. Lactate as an energy source is resynthesized to glucose in the liver and muscle or re-converted to pyruvate and constitutes an indispensable resource that is produced to satisfy rapid energy requirements. Because lactate is produced at high levels during continuous high-intensity exercise, it can be utilized as a fatigue marker to determine exercise intensity [ 35 , 36 ]. In particular, plasma lactate levels herein were significantly higher at IAE than at IAB and significantly lower at 30 MAE. However, no significant differences were observed among the groups, suggesting that one-bout exercise can induce lactate accumulation regardless of aerobic fitness level and C242T polymorphism status, as all subjects performed treadmill running at the exercise intensity corresponding to 85% VO 2 max. In particular, plasma lactate levels were increased as pyruvate production during glycolysis exceeded the maximum oxidizable amount in the mitochondria, with the increased pyruvate from lactate dehydrogenase catalysis consequently being converted to lactate. Concurrently, Ament and Verkerke [ 37 ] reported that rapid accumulation of blood lactate is generally observed when the exercise intensity increases and the switch from aerobic to anaerobic exercise metabolism occurs, which can be induced at 50% and 80% VO 2 max in both untrained and well-trained subjects relative to exercise intensity. The CYBA C242T polymorphism has been studied in patients with OS-related disorders, including cardiovascular disease, with the presence of the T allele among CC, CT, and TT genotypes, which are associated with lower superoxide production [ 12 , 13 ]. In comparison, this study analyzed plasma MDA levels and SOD activity to examine redox state biomarkers due to exhaustive aerobic fitness levels and the C242T polymorphism. We observed a significant increase in all groups in MDA levels at IAE, whereas only the two HF groups (CC + HF and T + HF) exhibited significant reductions at 30 MAE. Furthermore, these levels were significantly higher in the CC + MF group than in the T + HF group at IAE. These results suggested that high aerobic fitness and the presence of the T allele created an advantage compared to lower aerobic fitness and the CC genotype in alleviating OS levels, which increased after exhaustive one-bout exercise, thus supporting the previous findings that the T allele of the C242T polymorphism is associated with lower superoxide production than the CC genotype [ 18 , 19 , 20 ]. Moreover, MDA, 8-OHdG, and myeloperoxidase (MPO) are blood markers of acute exercise-induced OS levels [ 38 , 39 , 40 ]. Izzicupo et al. [ 41 ] conducted maximal stress tests using the Bruce protocol investigating the C242T polymorphism in 97 healthy long-distance runners. They reported that the T allele (CT/TT) is potentially associated with significantly lower MPO levels after exercise than the CC genotype and that T carriers are characterized by a significantly lower release of MPO [ 41 ]. Alternatively, the body has elaborate antioxidant defense systems to neutralize free radicals and ROS, with antioxidant enzymes, including SOD, catalase, and glutathione peroxidase [ 40 ]. SOD reportedly functions as an important antioxidant marker as it constitutes the first defense mechanism against superoxide radicals and is critical for converting superoxide radicals to H 2 O 2 and H 2 O [ 40 , 42 ]. In the present study, all groups displayed a significant increase in SOD activity at IAE and a significant reduction at 30 MAE. However, no significant differences between groups were observed, supporting previous studies that reported increased blood SOD activity after exercise [ 43 , 44 ] and that the activation of the antioxidant system increases to protect the body from oxidant damage due to one-bout exhaustive exercise. Specifically, Shin et al. [ 43 ] reported an increase in blood SOD activity after one-bout exercise that consumed 400 kcal at 60 and 80% of VO 2 max. Furthermore, Roh et al. [ 44 ] reported significantly increased blood SOD activities regardless of aerobic fitness level (54.3 ± 3.8 vs."},{"id":"source_9","type":"source","study":"A combination of ketones and NAD + precursor preserves white matter integrity in mild cognitive impairment","year":2026,"doi":"10.1002/trc2.70278","url":"https://doi.org/10.1002/trc2.70278","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Roy 2026","evidence_span":"Total gray matter ketone uptake increased by 2.4‐fold ( p < 0.001) in the active group, with no change in gray matter glucose uptake in either group. In WM, ketone uptake increased in the active group by 3.1–3.6‐fold across all seven tracts of interest ( p < 0.001). In the placebo group, myelin density declined by up to 10% in specific regions of the fornix ( p = 0.027), with no change in the active group.","excerpt":"Total gray matter ketone uptake increased by 2.4‐fold ( p < 0.001) in the active group, with no change in gray matter glucose uptake in either group. In WM, ketone uptake increased in the active group by 3.1–3.6‐fold across all seven tracts of interest ( p < 0.001). In the placebo group, myelin density declined by up to 10% in specific regions of the fornix ( p = 0.027), with no change in the active group."},{"id":"source_10","type":"source","study":"Nicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial","year":2023,"doi":"10.1038/s41598-023-29787-3","url":"https://doi.org/10.1038/s41598-023-29787-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Katayoshi 2023","evidence_span":"A total of 36 healthy middle-aged participants received one capsule of either 125 mg NMN or placebo twice a day. Among the NAD + metabolites, the levels of nicotinamide in the serum were significantly higher in the NMN intake group than in the placebo group. Pulse wave velocity values indicating arterial stiffness tended to decrease in the NMN intake group. However, no significant difference was found between the two groups. Long-term NMN supplementation at 250 mg/day was well tolerated and did not cause adverse events.","excerpt":"A total of 36 healthy middle-aged participants received one capsule of either 125 mg NMN or placebo twice a day. Among the NAD + metabolites, the levels of nicotinamide in the serum were significantly higher in the NMN intake group than in the placebo group. Pulse wave velocity values indicating arterial stiffness tended to decrease in the NMN intake group. However, no significant difference was found between the two groups. Long-term NMN supplementation at 250 mg/day was well tolerated and did not cause adverse events."},{"id":"source_11","type":"source","study":"Effects of Nicotinamide Adenine Dinucleotide on Older Patients with Heart Failure","year":2024,"doi":"10.31083/j.rcm2508297","url":"https://doi.org/10.31083/j.rcm2508297","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Pei 2024","evidence_span":"Based on using conventional drugs to treat HF, patients (n = 60) were randomized 1:1 to saline and 50 mg NAD + with 50 mL of normal saline for 7 days. The baseline characteristics of patients before and after treatment and cardiac function (N-terminal pro B-type natriuretic peptide (NT-proBNP) level and left ventricular ejection fraction (LVEF) value) were analyzed. Serological analysis (sirtuin-1 (SIRT1), sirtuin-3 (SIRT3), sirtuin-6 (SIRT6), reactive oxygen species (ROS), and endothelin) was also performed. Among the 60 patients with HF who were treated with NAD + for 7 days, the","excerpt":"Based on using conventional drugs to treat HF, patients (n = 60) were randomized 1:1 to saline and 50 mg NAD + with 50 mL of normal saline for 7 days. The baseline characteristics of patients before and after treatment and cardiac function (N-terminal pro B-type natriuretic peptide (NT-proBNP) level and left ventricular ejection fraction (LVEF) value) were analyzed. Serological analysis (sirtuin-1 (SIRT1), sirtuin-3 (SIRT3), sirtuin-6 (SIRT6), reactive oxygen species (ROS), and endothelin) was also performed. Among the 60 patients with HF who were treated with NAD + for 7 days, the improvement rate in NT-proBNP levels and LVEF values was better than in the saline group, although not statistically significant. These patients were more likely to benefit from NAD + because of higher levels of anti-oxidative stress (SIRT1, SIRT3, SIRT6, and ROS) and anti-endothelial injury (endothelin) than those in the saline control group. According to the results of this study, it is believed that 7 days of NAD + injections has a positive effect on improving cardiac function, oxidative stress, and endothelial injury in patients with HF compared with the saline control. Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ ) ChiCTR2300074326; retrospectively registered on 3 August 2023. Keywords: heart failure, NAD + , clinical study, adjuvant therapy Heart failure (HF) poses a serious threat to human health and is characterized by high morbidity, high mortality, a high rehospitalization rate, and many high-risk groups. The American Heart Association/American College of Cardiology guidelines define HF as “a complex clinical syndrome caused by any structural or functional heart disease that affects the ability of the ventricles to fill and shoot blood” [ 1 ]. Benjamin et al . [ 2 ] reported that patients hospitalized for HF are at an increased risk of HF rehospitalization and cardiovascular death. One in eight deaths is due to HF, and the mortality rate within 5 years of diagnosis is as high as 50%, exceeding that of some malignancies [ 2 ]. Despite the increased number of drugs used to treat HF, the fatality rate remains high. The 2021 European Society of Cardiology guidelines recommend a combination of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin-receptor neprilysin inhibitor, β -blockers, and aldosterone receptor antagonists (MRAs) as the primary treatment for chronic HF [ 3 ]. Both the previous “golden triangle” ( β -blocker, ACEI/angiotensin II receptor blocker [ARB], and MRA) and the current “five golden flowers” ( β -blocker, ACEI/ARB, MRA, and sodium-dependent glucose transporter 2 inhibitors) have limitations in clinical treatment [ 4 , 5 , 6 ]. Current drug therapy still cannot meet the needs of HF management, making it necessary to develop new treatment ideas and explore new treatment strategies. Nicotinamide adenine dinucleotide (NAD + ) is an important cofactor and a key metabolic enzyme substrate involved in redox reactions in the mitochondria, which is greatly significant in maintaining the balance of NAD + in vivo for normal human metabolism [ 7 ]. Several studies have shown that NAD + can inhibit inflammation and oxidative stress injury in endothelial cells, reduce apoptosis in microvascular endothelial cells, promote microangiogenesis, and improve microvascular injury caused by coronary microcirculation and myocardial ischemia-reperfusion [ 8 ]. Studies have also shown that the NAD + concentration in the blood of patients with HF is significantly lower than in healthy people, and with an increase in age, NAD + also has a trend of gradually decreasing [ 7 , 9 ]. Therefore, stabilizing intracellular NAD + levels through exogenous NAD + supplementation is expected to be a therapeutic strategy for improving cardiac bioenergetics and function. HF is the leading cause of hospitalization among older populations worldwide, with a high mortality rate and impact on the quality of life of patients [ 10 , 11 ]. With the development of medical technology, various drugs have emerged to treat HF. However, the effectiveness of these drugs remains unsatisfactory. HF remains an intractable disease, with an increased burden of hospitalization and a continuous loss of health care expenditure [ 12 ]. Therefore, it is necessary to identify alternative and complementary treatment options. Thus, we sought to evaluate whether NAD + therapy has some clinical efficacy in patients with HF. NAD + is widely present in the mitochondria of myocardial tissue, and NAD + activates the deacetylation activity of sirtuins, regulates the activity of numerous aging-related transcription factors, and intervenes in aging and aging-related diseases [ 9 , 13 , 14 ]. Several studies have shown that NAD + has beneficial effects on cardiovascular diseases by regulating metabolism, maintaining redox homeostasis, and modulating immune responses [ 15 , 16 , 17 ]. Studies have found that NAD + levels are significantly reduced in patients with HF [ 18 , 19 ]. In a rat model of myocardial infarction, compared with the LCZ696-positive drug control group, using NAD + improved some cardiac function and hemodynamic indexes and could further increase the left ventricular stroke output and systolic and diastolic blood pressure [ 20 ]. In the present clinical trial, we tested whether using exogenous NAD + supplementation as a new adjuvant treatment for HF is possible. NT-proBNP and LVEF are the most widely used laboratory indices for evaluating HF severity and prognosis. In our clinical trial, NT-proBNP levels improved in both groups, possibly because patients in both groups were rigorously treated with anti-HF drugs. However, the improvement was more obvious in the NAD + group than in the saline control group, which better reflects that the therapeutic effect of NAD + in patients with HF is independent of conventional medication for HF. Although the NT-proBNP level in the NAD + group improved from baseline, no statistically significant difference was found over time. This finding may be due to the large dispersion of the data, short treatment course, and small sample size; similarly, due to short-term drug use, changes in the structure and function of the heart cannot be obvious over a short time. Moreover, the measurement of LVEF is subjective to a certain extent and is related to the experience of the tester. LVEF in the NAD + group was improved, with no statistical difference between the groups. Studies have found that women may have lower NAD + concentrations and benefit most from improved heart function [ 21 , 22 ]. In our study, there was no statistical difference in gender between the two groups of patients, and whether women can benefit more from NAD + treatment will be our major direction in the future. Oxidative stress plays an important role in HF occurrence and progression [ 23 ]. The sirtuin family is also linked to several antioxidant and oxidative stress-related processes and functions [ 24 ]. Sirtuins are a family of seven enzymes (sirtuin1–7) involved in regulating many metabolic processes [ 25 ]. Sirtuin agonists are more convincing than existing deacetylase inhibitors for the treatment of cardiovascular diseases in terms of safety and efficacy and may have clinical value for treating multiple types of cardiovascular diseases [ 26 ]. Increasing the NAD + level in vivo can activate sirtuins, which can significantly inhibit myocardial hyperacetylation and improve myocardial mitochondrial function [ 27 ]. Clemency et al . [ 28 ] found that sodium-glucose cotransporter 2 (SGL-2) inhibitor could inhibit oxidative stress by increasing the expression of SIRT1 and SIRT3 and decreasing the expression of SIRT6, thereby alleviating myocardial injury. In our clinical trial, the SIRT1, SIRT3, and SIRT6 levels increased at the 2-week follow-up after medication, but over time, the concentration of exogenous supplemental NAD + gradually decreased in vivo and showed a trend of gradual decrease in the last two follow-up visits, which is also consistent with the metabolic process of intravenous drug use in the body. Furthermore, there was an interaction between SIRT1 in the saline control group and the NAD + group, which confirmed that NAD + plays a critical role in anti-oxidative stress. We observed that ROS levels increased in the NAD + group at the 2-week follow-up visit, possibly due to the negative feedback reaction of inflammation caused by the strong antioxidant effect in the short term. However, those levels improved at later visits. Increased levels of ET, the most potent vasoconstrictor, are produced by the pro-peptide precursor, large ET, through ET convertase [ 29 ]. ET in the peripheral blood of patients with HF can predict poor prognosis [ 30 , 31 , 32 ]. In this clinical trial, there were significant differences in ET levels between the saline control and NAD + groups, which confirmed that NAD + plays a more critical role in anti-endothelial injury. Although there was no difference in the incidence of composite endpoint events (including all-cause death and readmission due to HF) during the 1-year follow-up period in this study, there was still a significant difference in mortality between the two groups. The survival rate of NAD + was higher, and most patients who died were in the saline control group, usually 2–4 months after treatment. These results suggest that the use of NAD + may delay the progression of HF and reduce short-term mortality. The reason why no statistical difference was found in the various clinical endpoints in this study may be related to the small number of study cases, the short duration of NAD + administration, and the short follow-up time. Nevertheless, this study has expanded our ideas for exploring new treatments for patients with HF and confirmed their therapeutic effect on patients with HF based on molecular biology and echocardiography evaluation indicators. We also expect this study’s results to guide follow-up national multicenter, large-sample, prospective, randomized, double-blind controlled studies. We further confirmed the therapeutic effects of NAD + in the HF population. According to the product instructions, NAD + occasionally has side effects such as dry mouth, nausea, dizziness, and palpitations. However, in this clinical trial, patients had no obvious complaints after 7 days of intravenously administering NAD + , but the long-term effect or safety of treatment still needs to be observed over a longer study period. In addition, the follow-up of participants after completing this clinical trial may be limited, making it difficult to assess long-term outcomes and treatment safety. Our study consisted of a small sample size from a single center, potentially limiting the generalizability of our findings to a broader population of HF patients. Future multicenter studies covering cohorts with different demographic and clinical characteristics would help validate our findings and enhance external validity. In addition, we did not perform cardiovascular magnetic resonance to assess patients with HF more comprehensively. We did not discuss the pharmacological background of HF patients further, and our future research direction will be to focus on their pharmacological background. Among patients with HF, those injected with NAD + for 7 days may benefit more from improved cardiac function, levels of anti-oxidative stress, and endothelial injury than those re"},{"id":"source_12","type":"source","study":"Oral MIB‐626 (β Nicotinamide Mononucleotide) Safely Raises Blood Nicotinamide Adenine Dinucleotide Levels in Hospitalized Patients With COVID‐19 and Acute Kidney Injury: A Randomized Controlled Trial","year":2025,"doi":"10.1096/fba.2025-00014","url":"https://doi.org/10.1096/fba.2025-00014","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Pencina 2025","evidence_span":"To determine whether MIB‐626 ( β‐ nicotinamide mononucleotide), an NAD + precursor, can safely increase blood NAD + levels and attenuate acute kidney injury (AKI) and inflammation in hospitalized patients with COVID‐19, 42 adults, ≥ 18 years, hospitalized with COVID‐19 and AKI, were randomized in a 3:2 ratio to MIB‐626 1.0‐g or placebo tablets twice daily for 14 days. Circulating NAD + and its metabolites, markers of AKI, inflammation, and disease severity, were assessed. MIB‐626 treatment significantly but gradually raised blood NAD + levels to a peak between 5 to 14 days (16.0 ± 6.9, 25.5 ±","excerpt":"To determine whether MIB‐626 ( β‐ nicotinamide mononucleotide), an NAD + precursor, can safely increase blood NAD + levels and attenuate acute kidney injury (AKI) and inflammation in hospitalized patients with COVID‐19, 42 adults, ≥ 18 years, hospitalized with COVID‐19 and AKI, were randomized in a 3:2 ratio to MIB‐626 1.0‐g or placebo tablets twice daily for 14 days. Circulating NAD + and its metabolites, markers of AKI, inflammation, and disease severity, were assessed. MIB‐626 treatment significantly but gradually raised blood NAD + levels to a peak between 5 to 14 days (16.0 ± 6.9, 25.5 ± 12.6, and 42.6 ± 25.6 μg/mL at baseline, days 5 and 14) and raised plasma concentrations of NAD + metabolites 1‐methylnicotinamide, N‐methyl, 2‐pyridone, 4‐carboxamide rapidly to a peak by day 3. Changes in serum creatinine, cystatin‐C, and serum markers of AKI did not differ significantly between groups. Serum CRP, IL‐6, and TNFα and indices of disease severity also did not differ between groups. MIB‐626 treatment of patients with COVID‐19 and AKI safely and substantially raised blood NAD + and plasma concentrations of NAD + metabolites. Markers of AKI, inflammation, and disease severity did not differ between groups, likely due to the slow rise in NAD + levels. Future studies should assess whether a rapid increase in NAD + by parenteral administration can attenuate disease severity and AKI. Trial Registration: ClinicalTrials.gov Identifier: NCT05038488 Keywords: acute kidney injury, COVID‐19, NAD augmentation, NAD metabolism, NAD precursor, nicotinamide mononucleotide This placebo‐controlled, randomized, parallel group, double‐blind trial was conducted at 3 trial sites: Brigham and Women's Hospital in Boston, MA; University of Texas Medical Branch, Galveston, TX; and Tulane University Medical Center, New Orleans, LA. The study protocol was approved by the trial's single institutional review board (sIRB) at the Mass General Brigham Human Research Protection Program and the institutional review boards of the participating trial sites ceded to the sIRB. An independent Data and Safety Monitoring Board (DSMB) reviewed the safety data and study progress every 6 weeks to 3 months. The participants provided consent and authorization for the use and disclosure of personal health information in accordance with the Health Insurance Portability and Accountability Act. The trial was registered at ClinicalTrials.gov . This is the first randomized, placebo‐controlled trial of NAD + augmentation in patients hospitalized with moderately severe SARS‐CoV‐2 infection to show that MIB‐626 was safe, well tolerated, and efficacious in raising blood NAD + levels in patients with COVID‐19. The present study also shows that blood NAD + levels are only modestly lower in patients with COVID‐19 compared to healthy adults without COVID‐19 but that the circulating concentrations of NAD + metabolites such as MeNAM, NAM, and 2‐PY are markedly increased in patients with COVID‐19 compared with healthy adults, suggesting increased turnover of NAD + due to marked upregulation of enzymes involved in NAD consumption as well as synthesis, as suggested by our previous observational study of patients with COVID‐19 [ 16 ]. In spite of the increased NAD + turnover during acute COVID‐19, the MIB‐626 regimen used in this study (1.0 g twice daily) significantly raised NAD + levels, although the increment above baseline was lower than that observed in our previous studies in healthy adults with a similar dose regimen [ 18 , 19 ]. Consistent with our previous phase 1 studies [ 18 , 19 ], blood NAD + levels rose gradually in MIB‐626‐treated patients and reached the peak steady state levels between days 5 and 14, even though the plasma levels of its metabolites, MeNAM and 2‐PY, reached peak levels by day 3, which was the earliest sampling time point after randomization. The reasons for the slow ramp up of blood NAD + levels in spite of a more rapid increase in circulating levels of its metabolites after oral NMN administration are not clear. It is possible that a longer time period is required to reach peak steady state levels due to the substantially increased NAD + turnover in patients with COVID‐19. The mechanisms by which oral NAD + precursors, NMN and NR, increase blood and tissue NAD + levels need further investigation by metabolic flux studies using stable isotope‐labeled NAD + precursors. This relatively small trial did not reveal significant differences in serum creatinine or cystatin C or other serum markers of acute kidney injury, or in other clinical indices of disease severity. Due to the small sample size and substantial variability in the study's clinical endpoints in acutely ill patients with multiple comorbidities, the study likely did not have sufficient statistical power to detect meaningful differences in these endpoints. It took more than 5 days to achieve peak NAD + levels by which time, many patients had been discharged and this may have obscured the drug's efficacy."},{"id":"source_13","type":"source","study":"Comparative lipidomics and NAD⁺ metabolism in pectoris muscle reveal a lean metabolic phenotype in Daweishan miniature chickens versus arbor acre broilers","year":2026,"doi":"10.1016/j.psj.2026.106931","url":"https://doi.org/10.1016/j.psj.2026.106931","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Wu 2026","evidence_span":"Similarly, NAD⁺ and its intermediates (nicotinamide, nicotinamide mononucleotide, and nicotinamide riboside) concentrations were also higher in the M3 group compared to the A3 group ( p < 0.05). In addition, the enzymatic activities of SIRT1, LKB1, and AMPK were also greater in the M3 group than the A3 group ( p < 0.05).","excerpt":"Similarly, NAD⁺ and its intermediates (nicotinamide, nicotinamide mononucleotide, and nicotinamide riboside) concentrations were also higher in the M3 group compared to the A3 group ( p < 0.05). In addition, the enzymatic activities of SIRT1, LKB1, and AMPK were also greater in the M3 group than the A3 group ( p < 0.05)."},{"id":"source_14","type":"source","study":"Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin","year":2022,"doi":"10.1111/acel.13754","url":"https://doi.org/10.1111/acel.13754","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Vreones 2022","quote":"Here, we studied biomarkers in plasma extracellular vesicles enriched for neuronal origin (NEVs) from 22 healthy older adults who participated in a randomized, placebo‐controlled crossover trial ( NCT02921659 ) of oral NR supplementation (500 mg, 2x /day, 6 weeks).","evidence_span":"Here, we studied biomarkers in plasma extracellular vesicles enriched for neuronal origin (NEVs) from 22 healthy older adults who participated in a randomized, placebo‐controlled crossover trial ( NCT02921659 ) of oral NR supplementation (500 mg, 2x /day, 6 weeks).","excerpt":"Here, we studied biomarkers in plasma extracellular vesicles enriched for neuronal origin (NEVs) from 22 healthy older adults who participated in a randomized, placebo‐controlled crossover trial ( NCT02921659 ) of oral NR supplementation (500 mg, 2x /day, 6 weeks)."},{"id":"source_15","type":"source","study":"An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers","year":2017,"doi":"10.1371/journal.pone.0186459","url":"https://doi.org/10.1371/journal.pone.0186459","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Airhart 2017","quote":"Significant increases comparing baseline to mean concentrations at steady state (C ave,ss ) were observed for both NR ( p = 0.03) and NAD+ ( p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R 2 = 0.72, p = 0.008).","evidence_span":"Significant increases comparing baseline to mean concentrations at steady state (C ave,ss ) were observed for both NR ( p = 0.03) and NAD+ ( p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R 2 = 0.72, p = 0.008).","excerpt":"Significant increases comparing baseline to mean concentrations at steady state (C ave,ss ) were observed for both NR ( p = 0.03) and NAD+ ( p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R 2 = 0.72, p = 0.008). Because NR increases circulating NAD+ in humans, NR may have potential as a therapy in patients with mitochondrial dysfunction due to genetic and/or acquired diseases. Mitochondrial dysfunction has been implicated in multiple diseases, including heart failure [ 1 – 3 ]. However, there currently is no specific treatment for mitochondrial dysfunction in human heart failure or any other disease [ 4 – 7 ]. In recent years, there has been a surge of interest in targeting alterations in energy metabolism in heart failure. Development of mitochondria-based therapies for metabolic diseases has been hampered both by limited understanding of how mitochondrial impairment causes tissue dysfunction as well as by a lack of interventions shown to improve mitochondrial function. Recently, we demonstrated in a murine model that impaired mitochondrial oxidative phosphorylation led to an increased myocardial NADH/NAD+ ratio and increased mitochondrial protein acetylation without affecting mitochondrial production of reactive oxygen species (ROS) or synthesis of adenosine triphosphate (ATP) [ 8 ]. These changes rendered the heart susceptible to chronic stresses, which accelerated the development of heart failure. Similar increases in the NADH/NAD+ ratio and in protein acetylation also were seen in animal models of heart failure due to chronic pressure overload. Furthermore, intraperitoneal administration of the NAD+ precursor nicotinamide mononucleotide (NMN) to these mice normalized the NADH/NAD+ ratio, prevented the increase in mitochondrial protein acetylation, and improved cardiac function [ 9 ]. Promoting NAD+ synthesis through the salvage pathway by overexpressing nicotinamide phosphoribotransferase protected against ischemia-reperfusion injury and ischemic heart failure [ 10 , 11 ]. These findings collectively suggest that augmentation of NAD+ could improve mitochondrial function and exert myocardial protection. Nicotinamide riboside (NR) is a pyridine nucleoside form of vitamin B3 that is naturally found in milk and is available as a nutraceutical. NR is converted by nicotinamide riboside kinases (NRK1,2) to NMN, which is subsequently converted to NAD+ by nicotinamide mononucleotide adenylyltransferase (NMNAT). Oral supplementation with NR has been shown to increase NAD+ in brown adipose tissue, skeletal muscle and liver, and to improve mitochondrial function in a mouse model of diet-induced obesity [ 12 ]. Nutritional supplementation with NR, an NAD+ precursor, thus holds potential as an innovative therapy for heart failure and other disease states characterized by mitochondrial dysfunction. However, very limited information is available in regard to whether NR supplementation augments NAD+ levels in humans. Therefore, the primary objective of this study was to determine the pharmacokinetics of orally administered NR and its ability to increase blood NAD+ in healthy subjects following dose escalation of NR to 1000 mg twice daily. Primary outcomes were comparisons of baseline concentrations versus mean concentrations at steady state (C ave,ss ) on Day 9 for NR and NAD+. Secondary outcomes were to determine the safety and tolerability of NR by assessing adverse event rates and comparisons of laboratory tests, specifically serum levels of potassium, creatine kinase (myositis), glucose (insulin resistance), uric acid and alanine aminotransferase. During assay development before starting the study, NR was found to be highly unstable in blood, although the combination of 2.5 M citric acid and ACD solution improved NR stability in blood. At room temperature, the absolute peak heights of NR and the deuterated internal standard spiked into blood and processed as described in the methods section decreased by 8% to 14% over 30 min, but their ratios remained constant. While the latter observation means quantitation relying on signal ratio between analyte and internal standard is feasible in the event of ex vivo degradation or consumption, the decrease in absolute signal does limit our assay sensitivity (i.e., LLOQ). At the temperature of wet ice, spiked NR and deuterated internal standard appeared stable for 20 min, but decreased by 22% in 1 hour. This led to our current practice of processing the blood samples immediately to limit the lapse between blood draw and stabilization to < 5 min. NR in the sample becomes stable once blood proteins are precipitated, which allowed us to process the samples on the LC-MS/MS over the required run time. Also, storage data thus far indicate that NR blood samples are stable at –80°C for at least 3 weeks. With the resolution of NR’s instability problem, we were able to generate for the first time pharmacokinetic data on NR in human subjects. It should also be noted that we did try to measure NR in the plasma fraction of a few blood samples obtained from volunteers following ingestion of NR, but failed to detect measurable levels of the riboside. We concluded that NR is concentrated in the cellular fraction of blood. Because NR’s instability in blood ex vivo, we decided to avoid the delay in separating cells from blood samples, and instead assay whole blood concentration. Similar to NR, NAD+ is unstable in blood samples at room temperature. Measured levels of NAD+ spiked into thawed, room-temperature whole blood degraded by as much as 50% in 10 minutes. NAD+ degraded at a much slower rate (~3–4% decrease in 10 minutes) when blood samples were placed on wet ice. Also, NAD+ is stable in blood when stored at –80°C for at least 3 weeks. Hence, blood samples collected for NAD+ analysis were immediately placed on wet ice and then frozen in dry ice within 5 minutes of collection. Once blood proteins were precipitated with TCA, NAD+ in the supernatant remained stable for at least 48 hours while the samples were being processed on the LC-MS. Also, instability, at least over a few hours, was not observed when NAD+ was spiked into BSA rather than blood, suggesting that the disappearance of signal is not due to chemical instability. This pilot study yielded several important findings. First, successful and reliable methods for collection, processing and measurement of NR and NAD+ in human blood were developed, overcoming the severe instability problems that have prevented previous investigations into the clinical pharmacokinetics of NR in blood or tissue. These methods allowed us to determine the pharmacokinetic profile of orally administered NR in healthy human volunteers. Second, the study demonstrated that an NR dose of 1000 mg twice daily significantly increased steady-state, whole-blood levels of NAD+ in all study participants with individual increases ranging from 35–168% above baseline NAD+ levels. Finally, the study demonstrated that measurable, biologic effects on NAD+ levels can be achieved in healthy volunteers at NR doses that are well-tolerated. Specifically, participants reported none of the serious side effects seen with similar doses of niacin, such as flushing, pruritus, hyperglycemia, hyperuricemia, or elevations in liver or muscle enzymes [ 17 , 18 ]. Together, these findings support the feasibility of studying NR as a potential therapy for diseases in which mitochondrial dysfunction has been implicated. At the time of our manuscript submission, Trammell et al. [ 16 ] reported a similar study on NAD+ metabolome in peripheral blood mononuclear cells (PBMC) in twelve healthy human subjects after single oral ingestion of NR at three different dose levels: 30, 100 and 1000 mg. Their findings are consistent with our experience and observations after 9 consecutive days of NR treatment at a final daily dose of 1000 mg. Over the 36 days of observation, Trammell et al. did not observe any serious adverse event and any event that was dose-related. Mean PBMC NAD+ concentration at 24-hours for pooled data across all three dose levels was significantly elevated compared to pre-dose concentration (p ≤ 0.03)."},{"id":"source_16","type":"source","study":"Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD + in healthy middle-aged and older adults","year":2018,"doi":"10.1038/s41467-018-03421-7","url":"https://doi.org/10.1038/s41467-018-03421-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Martens 2018","evidence_span":"A follow-up analysis suggested that this trend was most pronounced in individuals with baseline BP between 120 and 139 mmHg, a subgroup currently classified clinically as having either “elevated” SBP (120–129 mmHg) or stage 1 systolic hypertension (130–139 mmHg). The mean decrease in SBP after NR treatment in this subgroup approached 10 mmHg—a magnitude of change associated with a 25% decrease in incident CV events in a recent major anti-hypertensive drug trial in older adults 44 . If this magnitude of SBP reduction with NR supplementation is confirmed in a larger clinical trial, such an","excerpt":"A follow-up analysis suggested that this trend was most pronounced in individuals with baseline BP between 120 and 139 mmHg, a subgroup currently classified clinically as having either “elevated” SBP (120–129 mmHg) or stage 1 systolic hypertension (130–139 mmHg). The mean decrease in SBP after NR treatment in this subgroup approached 10 mmHg—a magnitude of change associated with a 25% decrease in incident CV events in a recent major anti-hypertensive drug trial in older adults 44 . If this magnitude of SBP reduction with NR supplementation is confirmed in a larger clinical trial, such an effect could have broad biomedical implications. SBP in this range (120−139 mmHg) is observed in ~50% of all middle-aged and older adults in the U.S. 45 Moreover, SBP < 140 mmHg is responsible for at least one-third of all BP-attributable deaths 46 and is associated with increased risk of heart disease, stroke, cognitive impair"},{"id":"source_17","type":"source","study":"Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD + Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures","year":2019,"doi":"10.1016/j.celrep.2019.07.043","url":"https://doi.org/10.1016/j.celrep.2019.07.043","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"direct","cited_as":"Elhassan 2019","evidence_span":"Using a robust clinical trial design, we show that 21 days of NR supplementation is safe and well tolerated in an aged male cohort and leads to an augmented NAD + metabolome in whole blood, corroborating data recently reported by others ( Martens et al., 2018 , Trammell et al., 2016a ). The median BMI in this trial is 26.6 kg/m 2 (i.e., slightly overweight), but this is highly prevalent in aged populations ( Winter et al., 2014 ) and may not indicate an unhealthy state ( Porter Starr and Bales, 2015 ). Experiments in genetic mouse models have shown that oral NR is available to cardiac (","excerpt":"Using a robust clinical trial design, we show that 21 days of NR supplementation is safe and well tolerated in an aged male cohort and leads to an augmented NAD + metabolome in whole blood, corroborating data recently reported by others ( Martens et al., 2018 , Trammell et al., 2016a ). The median BMI in this trial is 26.6 kg/m 2 (i.e., slightly overweight), but this is highly prevalent in aged populations ( Winter et al., 2014 ) and may not indicate an unhealthy state ( Porter Starr and Bales, 2015 ). Experiments in genetic mouse models have shown that oral NR is available to cardiac ( Diguet et al., 2018 ) and skeletal ( Frederick et al., 2016 ) muscle, though it was also suggested that the benefit of extrahepatic NAD + from oral NR is mediated by circulating NAM ( Liu et al., 2018 ). Here, we show that oral NR increased human skeletal muscle NAAD, which was previously reported as a more sensitive marker of increased NAD + metabolism than NAD + per se ( Trammell et al., 2016a ), as well as MeNAM, Me-4-py, and Me-2-pywithout a rise in circulating NAM. Previous preclinical studies have established that oral NR is able to functionally restore muscle NAD + despite a loss of NAM salvage ( Frederick et al., 2016 , Diguet et al., 2018 ). Although it is clear in rodent models that NR requires NR kinase activity in muscle ( Ratajczak et al., 2016 , Fletcher et al., 2017 ), further studies are required to understand NR dynamics in human muscle cells and tissues. Increased circulating levels of MeNAM and expression of its generating enzyme nicotinamide-N-methyltransferase (NNMT) have been associated with insulin resistance and type 2 diabetes ( Kannt et al., 2015 , Liu et al., 2015 ). However, the NR-mediated abundance of MeNAM did not alter glucose tolerance or substrate utilization in our study. The levels of elevated NAM excretory products in skeletal muscle may be a result of pre-existing NAD + sufficiency in this aged cohort and may explain the lack of effect on mitochondrial, physiological, and cardiometabolic parameters. A limited number of studies have reported minor age-related declines in NAD + in human tissues ( Massudi et al., 2012 , Chaleckis et al., 2016 , Zhou et al., 2016 , Clement et al., 2018 ), but these data are non-conclusive. It is likely that a “second hit” arises during chronological aging that leads to tissue NAD + decline and predisposes to age-related disease and frailty. This “second hit” may be conditions of metabolic stresses such as physical inactivity, chronic inflammation, or presence of a pre-existing cardiometabolic disease (e.g., obesity), and it may implicate downregulated NAMPT ( Costford et al., 2010 , Imai and Yoshino, 2013 ), depressed hepatic NADP(H) ( Trammell et al., 2016b ), and/or activation of CD38 ( Camacho-Pereira et al., 2016 , Covarrubias et al., 2019 ). Clearly, more human data are needed to delineate the relationship between aging and NAD + metabolism. We note a median hand-grip strength in our participants of 33.8 kg of force, consistent with muscle aging for men in their eighth decade and likely associated impairment in mitochondrial function. Our data suggest that 3 weeks of NR supplementation without concomitant muscle training is insufficient for increased strength."}],"edges":[{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_1","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_2","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_3","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_4","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_5","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_6","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_7","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_8","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_9","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_10","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_11","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_12","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_13","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_14","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_15","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_16","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_17","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_18","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_19","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_20","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_21","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_22","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_23","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_24","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_25","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_26","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_27","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_28","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_29","type":"contains_claim"},{"from":"9be40a10-b14d-4e4a-afff-f058a818c80b","to":"claim_30","type":"contains_claim"}],"screening":{"identified":17,"screened":17,"excluded":0,"included":17,"included_or_retained":17,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"17 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]}}},{"name":"contradiction_map.json","media_type":"application/json","content":{"publication_id":"9be40a10-b14d-4e4a-afff-f058a818c80b","screening":{"identified":17,"screened":17,"excluded":0,"included":17,"included_or_retained":17,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"17 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]},"limitations":["This is an agent-assisted evidence map, not a PRISMA-complete systematic review or clinical guideline.","It is not PROSPERO-registered and should not be read as medical advice.","Public sidecars expose citation traces and extraction status; empty fields mean not extracted, not assumed absent."],"contradictions":["Null findings have a specific role in this evidence model. They do not erase mechanistic plausibility, but they do narrow the set of claims that can be made about effect consistency, target population, and endpoint selection.","For instance, while one trial reported a trend toward improved NYHA class in heart failure patients [Yu 2025] [bundle:4], other trials in different populations found null effects on functional endpoints, such as mitochondrial respiration and skeletal muscle function in older adults [Connell 2021] [bundle:5] and cognition in long-COVID patients [Wu 2025] [bundle:1] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.1093/jn/nxab193] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633].","Null findings have a specific role in this evidence model. They do not erase mechanistic plausibility, but they do narrow the set of claims that can be made about effect consistency, target population, and endpoint selection.","For instance, while one trial reported a trend toward improved NYHA class in heart failure patients [Yu 2025] [bundle:4], other trials in different populations found null effects on functional endpoints, such as mitochondrial respiration and skeletal muscle function in older adults [Connell 2021] [bundle:5] and cognition in long-COVID patients [Wu 2025] [bundle:1] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.1093/jn/nxab193] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633].","The geroscience framework reframes the clinical challenge: rather than developing separate therapies for heart failure, atherosclerosis, and metabolic syndrome, one might target the shared biological substrate of aging itself. NAD+ precursors, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), represent a drug class that has moved rapidly from preclinical observation to human supplementation trials. The regulatory pathway for these compounds has been complex; they are often marketed as dietary supplements, which permits consumer access but limits the regulatory oversight and standardized dosing that characterize pharmaceutical development. Another trial demonstrated that a combination of nicotinamide and D-ribose (RiaGev) increased the NAD+ metabolome, with NADP+ rising by 27% compared to placebo after seven days of supplementation [Xue 2022] [bundle:7] [exact source: https://doi.org/10.3390/nu14112219]. These findings confirm that oral precursors can reliably raise circulating NAD+, but the critical question is whether this biochemical elevation translates into clinically meaningful cardiovascular protection.","A review of the human RCT landscape reveals a striking heterogeneity in study populations, interventions, and endpoints, with very few trials directly assessing cardiovascular outcomes. The most direct cardiovascular evidence comes from a trial in patients with heart failure caused by ischemic cardiomyopathy, where intravenous NAD+ was compared to placebo. This study reported a statistically significant improvement in left ventricular ejection fraction (LVEF) within the NAD+ group at one month, but the between-group comparison for New York Heart Association (NYHA) class improvement showed only a trend (P = 0.088 at one month, P = 0.115 at six months) [Yu 2025] [bundle:4] [exact source: https://doi.org/10.1007/s40256-025-00764-7]. A separate trial in older adults with heart failure found that seven days of intravenous NAD+ injection improved NT-proBNP levels and LVEF values compared to saline, although the differences were not statistically significant [Pei 2024] [bundle:11] [exact source: https://doi.org/10.31083/j.rcm2508297]. Other trials have examined NAD+ precursors in populations with acute kidney injury [Simic 2020 [bundle:3], Pencina 2025 [bundle:12]], long-COVID [Wu 2025] [bundle:1], sudden sensorineural hearing loss [Gao 2025] [bundle:2], and mild cognitive impairment [Roy 2026] [bundle:9], where cardiovascular endpoints were not the primary focus [exact source: https://doi.org/10.1186/s12882-020-02006-1] [exact source: https://doi.org/10.1096/fba.2025-00014] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633] [exact source: https://doi.org/10.1002/lary.70173] [exact source: https://doi.org/10.1002/trc2.70278]. This fragmentation of the evidence base means that any synthesis of cardiovascular effects must draw indirect inferences from trials designed for other purposes.","Several unresolved questions complicate the interpretation of the existing evidence. First, the mechanism by which elevated NAD+ might improve cardiac function remains poorly defined in humans; proposed pathways include enhanced mitochondrial bioenergetics, reduced oxidative stress, and improved endothelial function, but these are largely extrapolated from preclinical models. Second, the duration of supplementation in most trials is short—often weeks to a few months—raising the question of whether longer-term exposure is necessary for cardiovascular benefit or whether it introduces unforeseen risks. Third, dose-response relationships are unclear; trials have used a wide range of doses, from 250 mg/day of NMN [Katayoshi 2023] [bundle:10] to 1000 mg twice daily of NR [Airhart 2017] [bundle:15], and the optimal dose for cardiovascular protection is unknown [exact source: https://doi.org/10.1038/s41598-023-29787-3] [exact source: https://doi.org/10.1371/journal.pone.0186459]. Fourth, population specificity is a concern, as the most promising cardiovascular signals come from patients with established heart failure [Yu 2025 [bundle:4], Pei 2024 [bundle:11]], while trials in healthier populations have not demonstrated clear cardiovascular benefits [Martens 2018] [bundle:16] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.31083/j.rcm2508297] [exact source: https://doi.org/10.1038/s41467-018-03421-7]. Finally, the trade-off between potential benefits and safety in vulnerable populations, such as those with acute kidney injury, requires careful evaluation [Simic 2020 [bundle:3], Pencina 2025 [bundle:12]] [exact source: https://doi.org/10.1186/s12882-020-02006-1] [exact source: https://doi.org/10.1096/fba.2025-00014].","The current evidence base presents significant cross-outcome tensions that must be explicitly addressed. For instance, while one trial reported a trend toward improved NYHA class in heart failure patients [Yu 2025] [bundle:4], other trials in different populations found null effects on functional endpoints, such as mitochondrial respiration and skeletal muscle function in older adults [Connell 2021] [bundle:5] and cognition in long-COVID patients [Wu 2025] [bundle:1] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.1093/jn/nxab193] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633]. This synthesis will separate mechanistic evidence from clinical evidence, acknowledging that biochemical changes (for example, increased NAD+ levels) do not automatically confer clinical benefit. The structured evidence weighting will prioritize direct human RCT data with cardiovascular endpoints, while clearly delineating the indirect evidence from trials focused on other outcomes. The goal is to provide a transparent assessment of where the evidence is strong, where it is suggestive, and where significant gaps remain, particularly regarding the long-term cardiovascular effects of NAD+ precursor supplementation in diverse human populations.","The evidence profile indicates that the case for NAD+ precursors as cardiovascular therapeutics is currently incomplete. Mechanistic plausibility is supported by the central role of NAD+ in cellular metabolism and the consistent ability of oral precursors to raise circulating levels [Airhart 2017 [bundle:15], Xue 2022 [bundle:7]] [exact source: https://doi.org/10.1371/journal.pone.0186459] [exact source: https://doi.org/10.3390/nu14112219]. However, the human RCT evidence is sparse and mixed. Direct cardiovascular trials are limited to small studies in heart failure populations with short follow-up and non-significant or trend-level between-group differences [Yu 2025 [bundle:4], Pei 2024 [bundle:11]] [exact source: https://doi.org/10.1007/s40256-025-00764-7] [exact source: https://doi.org/10.31083/j.rcm2508297]. The broader trial landscape includes studies in non-cardiovascular populations where cardiovascular endpoints were not assessed or were secondary [Wu 2025 [bundle:1], Gao 2025 [bundle:2], Roy 2026 [bundle:9]] [exact source: https://doi.org/10.1016/j.eclinm.2025.103633] [exact source: https://doi.org/10.1002/lary.70173] [exact source: https://doi.org/10.1002/trc2.70278]. Furthermore, some trials in relevant populations, such as older adults, have failed to show functional benefits on muscle or mitochondrial endpoints [Connell 2021] [bundle:5] [exact source: https://doi.org/10.1093/jn/nxab193]. The boundary conditions for any potential benefit—including optimal dose, duration, patient selection, and the specific cardiovascular outcomes that might respond—remain to be established. This synthesis aims to map these boundaries by systematically evaluating the available evidence, highlighting both the promises and the significant uncertainties that currently define the field.","| NAD+ Cardiovascular Effects / Contextual Adjacent Evidence | n=7; claims=174 | positive=0, negative=0, null=1, mixed=0, unclear=6 (n=7) | 7 direct | limited corpus depth in this outcome class |","| NAD+ Cardiovascular Effects / Muscle Function | n=4; claims=100 | positive=0, negative=1, null=1, mixed=0, unclear=2 (n=4) | 4 direct | limited corpus depth in this outcome class |","| NAD+ Cardiovascular Effects / Animal/Preclinical Context | n=2; claims=27 | positive=0, negative=0, null=0, mixed=0, unclear=2 (n=2) | 2 mechanistic | limited corpus depth in this outcome class |","| NAD+ Cardiovascular Effects / Safety and Comorbidity | n=2; claims=52 | positive=0, negative=0, null=0, mixed=1, unclear=1 (n=2) | 2 direct | limited corpus depth in this outcome class |","| NAD+ Cardiovascular Effects / Cardiometabolic | n=1; claims=13 | positive=0, negative=1, null=0, mixed=0, unclear=0 (n=1) | 1 direct | single-source slice; hypothesis-generating |","| NAD+ Cardiovascular Effects / Dosing and Pharmacokinetics | n=1; claims=29 | positive=0, negative=0, null=0, mixed=0, unclear=1 (n=1) | 1 direct | single-source slice; hypothesis-generating |","Thesis:** Across 17 curated reference papers, the evidence base for NAD+ shows a context-dependent profile. Negative signals appear in: muscle function, cardiometabolic. Null findings dominate: Contextual Adjacent Evidence, muscle function. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The NAD+ broad aging-related case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established. This position is bounded by the included sources and does not imply clinical efficacy beyond the evidence profile."]}},{"name":"evidence_table.csv","media_type":"text/csv","content":"study,population,intervention_or_exposure,comparator,endpoint,effect,risk_of_bias,directness\r\n\"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,direct\r\nNAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,direct\r\n\"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,direct\r\n\"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,direct\r\n\"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,direct\r\n\"A randomized, controlled clinical trial demonstrates improved owner-assessed cognitive function in senior dogs receiving a senolytic and NAD+ precursor combination\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,indirect\r\n\"A Combination of Nicotinamide and D-Ribose (RiaGev) Is Safe and Effective to Increase NAD + Metabolome in Healthy Middle-Aged Adults: A Randomized, Triple-Blind, Placebo-Controlled, Cross-Over Pilot Clinical Trial\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,direct\r\nEffect of C242T Polymorphism in the Gene Encoding the NAD(P)H Oxidase p22 phox Subunit and Aerobic Fitness Levels on Redox State Biomarkers and DNA Damage Responses to Exhaustive Exercise: A Randomized Trial,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,direct\r\nA combination of ketones and NAD + precursor preserves white matter integrity in mild cognitive impairment,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,direct\r\n\"Nicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,direct\r\nEffects of Nicotinamide Adenine Dinucleotide on Older Patients with Heart Failure,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,direct\r\nOral MIB‐626 (β Nicotinamide Mononucleotide) Safely Raises Blood Nicotinamide Adenine Dinucleotide Levels in Hospitalized Patients With COVID‐19 and Acute Kidney Injury: A Randomized Controlled Trial,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,direct\r\nComparative lipidomics and NAD⁺ metabolism in pectoris muscle reveal a lean metabolic phenotype in Daweishan miniature chickens versus arbor acre broilers,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,indirect\r\nOral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,direct\r\n\"An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,direct\r\nChronic nicotinamide riboside supplementation is well-tolerated and elevates NAD + in healthy middle-aged and older adults,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,direct\r\nNicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD + Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,direct\r\n"},{"name":"risk_of_bias.json","media_type":"application/json","content":{"publication_id":"9be40a10-b14d-4e4a-afff-f058a818c80b","method_note":"Risk-of-bias fields are surfaced when supplied by the submitting agent; otherwise marked as not appraised in public sidecar.","sources":[{"study":"Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial","doi":"10.1016/j.eclinm.2025.103633","risk_of_bias":"not appraised in public sidecar","directness":"direct"},{"study":"NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial","doi":"10.1002/lary.70173","risk_of_bias":"not appraised in public sidecar","directness":"direct"},{"study":"Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI","doi":"10.1186/s12882-020-02006-1","risk_of_bias":"not appraised in public sidecar","directness":"direct"},{"study":"Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial","doi":"10.1007/s40256-025-00764-7","risk_of_bias":"not appraised in public sidecar","directness":"direct"},{"study":"NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults","doi":"10.1093/jn/nxab193","risk_of_bias":"not appraised in public sidecar","directness":"direct"},{"study":"A randomized, controlled clinical trial demonstrates improved owner-assessed cognitive function in senior dogs receiving a senolytic and NAD+ precursor combination","doi":"10.1038/s41598-024-63031-w","risk_of_bias":"not appraised in public sidecar","directness":"indirect"},{"study":"A Combination of Nicotinamide and D-Ribose (RiaGev) Is Safe and Effective to Increase NAD + Metabolome in Healthy Middle-Aged Adults: A Randomized, Triple-Blind, Placebo-Controlled, Cross-Over Pilot Clinical Trial","doi":"10.3390/nu14112219","risk_of_bias":"not appraised in public sidecar","directness":"direct"},{"study":"Effect of C242T Polymorphism in the Gene Encoding the NAD(P)H Oxidase p22 phox Subunit and Aerobic Fitness Levels on Redox State Biomarkers and DNA Damage Responses to Exhaustive Exercise: A Randomized Trial","doi":"10.3390/ijerph17124215","risk_of_bias":"not appraised in public sidecar","directness":"direct"},{"study":"A combination of ketones and NAD + precursor preserves white matter integrity in mild cognitive impairment","doi":"10.1002/trc2.70278","risk_of_bias":"not appraised in public sidecar","directness":"direct"},{"study":"Nicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial","doi":"10.1038/s41598-023-29787-3","risk_of_bias":"not appraised in public sidecar","directness":"direct"},{"study":"Effects of Nicotinamide Adenine Dinucleotide on Older Patients with Heart Failure","doi":"10.31083/j.rcm2508297","risk_of_bias":"not appraised in public sidecar","directness":"direct"},{"study":"Oral MIB‐626 (β Nicotinamide Mononucleotide) Safely Raises Blood Nicotinamide Adenine Dinucleotide Levels in Hospitalized Patients With COVID‐19 and Acute Kidney Injury: A Randomized Controlled Trial","doi":"10.1096/fba.2025-00014","risk_of_bias":"not appraised in public sidecar","directness":"direct"},{"study":"Comparative lipidomics and NAD⁺ metabolism in pectoris muscle reveal a lean metabolic phenotype in Daweishan miniature chickens versus arbor acre broilers","doi":"10.1016/j.psj.2026.106931","risk_of_bias":"not appraised in public sidecar","directness":"indirect"},{"study":"Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin","doi":"10.1111/acel.13754","risk_of_bias":"not appraised in public sidecar","directness":"direct"},{"study":"An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers","doi":"10.1371/journal.pone.0186459","risk_of_bias":"not appraised in public sidecar","directness":"direct"},{"study":"Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD + in healthy middle-aged and older adults","doi":"10.1038/s41467-018-03421-7","risk_of_bias":"not appraised in public sidecar","directness":"direct"},{"study":"Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD + Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures","doi":"10.1016/j.celrep.2019.07.043","risk_of_bias":"not appraised in public sidecar","directness":"direct"}]}}]}