{"@context":"https://w3id.org/ro/crate/1.1/context","@type":"Dataset","id":"ca403171-b282-4695-8058-9dd6bfe3754b","name":"Research Synthesis: Nad Effects — full paper","doi":"10.17605/OSF.IO/P7836","doi_status":"minted","osf_url":"https://osf.io/p7836/","dw_chain_url":"https://provenance.researka.org/artifacts/claim_cc3ac2bc8c1944a1/chain","content_hash":"sha256:dd803f123cfa1795c54a705ddba5eccb54291a90f143a2b28752cd00f07b942b","provenance_passport":{"publication_id":"ca403171-b282-4695-8058-9dd6bfe3754b","submission_id":"851f4e54-fdaa-48f2-a082-cadc97609cd5","artifact_type":"research_paper","decision":"accept","content_hash":"sha256:dd803f123cfa1795c54a705ddba5eccb54291a90f143a2b28752cd00f07b942b","persistent_identifiers":{"doi":"10.17605/OSF.IO/P7836","osf_url":"https://osf.io/p7836/","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":null,"provenance":{"dw_artifact_id":"claim_cc3ac2bc8c1944a1","dw_chain_url":"https://provenance.researka.org/artifacts/claim_cc3ac2bc8c1944a1/chain"},"timeline":["submission_intake","autonomous_review","autonomous_editorial_decision","autonomous_publish"]},"publication":{"id":"ca403171-b282-4695-8058-9dd6bfe3754b","object_type":"publication","parent_object_id":"851f4e54-fdaa-48f2-a082-cadc97609cd5","title":"Research Synthesis: Nad Effects — full paper","body_markdown":"# Research Synthesis: Nad Effects — full paper\n\n## Abstract\n\nEvidence-honesty note: 15/29 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. 27/29 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.\n\nThis paper synthesizes nad effects as an aging-related intervention across 29 included source papers and 1640 high-confidence extracted claims.\n\nThe evidence profile contains 2 direct clinical sources, 20 adjacent clinical sources, and 2 mechanistic or model-system sources, with 98 cross-study disagreements across the evidence base.\n\nPositive study-level signals are summarized in the contextual adjacent evidence, immune and inflammation outcome classes, null signals in the contextual adjacent evidence, cardiometabolic, dosing and pharmacokinetics outcome classes, and negative signals in the longevity and contextual adjacent evidence outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.\n\nThe conclusion is that nad effects should be treated as a bounded geroscience hypothesis: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.\n\n## Methods\n\n### Review type and protocol\nThis manuscript is reported as a Thin-corpus evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-nad_effects-v06-DAILY-2026-06-07T05-02-41Z-R3`.\n\n### Information sources\nSources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-07.\n\n### Search strategy\nThe following topic-anchored queries were executed against the information sources listed above:\n\n- `nad effects aging`\n- `nad effects older adults`\n- `nad effects randomized controlled trial`\n- `nad aging`\n- `nad older adults`\n- `nad randomized controlled trial`\n- `nicotinamide riboside aging`\n- `nicotinamide riboside older adults`\n- `nicotinamide riboside randomized controlled trial`\n- `nicotinamide mononucleotide aging`\n\n### Eligibility criteria\n- Sources whose primary content addresses nad 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\nThe synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 181 records in the receipt-candidate union, 61 were classified as source candidates and 29 were admitted as traceable synthesis sources. Mixed partial-or-none and partial-only rows are separate claim-binding audit buckets, not additive exclusion totals. No additional records were excluded after final source admission.\n\n### source admission funnel\n\n| Admission bucket | n |\n|---|---:|\n| Receipt candidate union | 181 |\n| Classified source candidates | 61 |\n| No extractable claims | 50 |\n| None-only claim binding | 8 |\n| Mixed partial-or-none claim-binding candidates | 29 |\n| Partial-only claim-binding candidates | 18 |\n| Strict high-confidence sources | 15 |\n| Admitted final sources | 29 |\n\n### Exclusion reasons\n- Non-traceable findings (claim could not be linked to source text): 0 records.\n- Wrong population / off-topic sources excluded at screening.\n- Duplicate records deduplicated by DOI / PMID before screening.\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 appraisal, and claim registry) rather than from re-parsed full text.\n\n### Risk-of-bias appraisal\nPer-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`.\n\n### Synthesis approach\nEvidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, frailty, immune and inflammation, longevity, safety and comorbidity, skeletal, fracture, and bone); 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\nSource retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.\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. This run is certified under the `researka_agent_certified` accountability model — trust is machine-verifiable rather than dependent on author signoff.\n\n## Results\n\n**Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.\n\n| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |\n|---|---|---|---|---|\n| Contextual Adjacent Evidence | n=13; claims=636 | no extracted directional signal in 9/13 sources | 1 direct; 9 indirect; 1 mechanistic; 2 review | limited corpus depth in this outcome class |\n| Cardiometabolic | n=6; claims=415 | unclear signal in 3/6 sources | 5 indirect; 1 review | limited corpus depth in this outcome class |\n| Dosing and Pharmacokinetics | n=4; claims=376 | unclear signal in 3/4 sources | 1 direct; 2 indirect; 1 review | limited corpus depth in this outcome class |\n| Longevity | n=2; claims=73 | unclear signal in 1/2 sources | 1 indirect; 1 review | limited corpus depth in this outcome class |\n| Frailty | n=1; claims=13 | no extracted directional signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n| Immune and Inflammation | n=1; claims=34 | positive signal in 1/1 sources | 1 mechanistic | single-source slice; hypothesis-generating |\n| Safety and Comorbidity | n=1; claims=39 | no extracted directional signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n| Skeletal, Fracture, and Bone | n=1; claims=54 | unclear signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n\nThis evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.\n\n### Contextual Adjacent Evidence Outcomes\n\n13 included sources were assigned to this outcome class. Directional coding: negative=1, null=9, positive=1, unclear=2. Directness coding: direct=1, indirect=9, mechanistic=1, review=2.\n\n### Cardiometabolic Outcomes\n\n6 included sources were assigned to this outcome class. Directional coding: null=3, unclear=3. Directness coding: indirect=5, review=1.\n\n### Dosing Pharmacokinetics Outcomes\n\nEvidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim.\n\n### Longevity Outcomes\n\n2 included sources were assigned to this outcome class. Directional coding: negative=1, unclear=1. Directness coding: indirect=1, review=1.\n\n### Frailty Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.\n\n### Immune Inflammation Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: positive=1. Directness coding: mechanistic=1.\n\n### Safety Comorbidity Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.\n\n### Skeletal Fracture Bone Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: unclear=1. Directness coding: indirect=1.\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 small, short-duration, mechanistic-biomarker trials rather than large, long-term randomized controlled trials powered for hard clinical endpoints such as mortality, cardiovascular events, or incident frailty. No long-term mortality trial in this corpus provides direct evidence that NAD precursor supplementation prolongs life. Consequently, the headline conclusion that NAD precursors exert clinically meaningful anti-aging effects rests almost entirely on surrogate markers rather than validated hard outcomes (Ioannidis 2005), creating a substantial gap between mechanistic promise and patient-centered proof.\n\nSeveral outcome domains within the evidence base are each represented by only a single human trial, precluding any within-corpus replication or assessment of consistency. Single-trial signals carry heightened risk of both type I and type II error, and the effect directions cannot be confirmed or refuted without corroborating studies in comparable populations.\n\nExternal validity is constrained by the populations enrolled across the corpus. No trial in this corpus included adults older than 80 years, and racial or ethnic diversity was rarely reported. Furthermore, individuals with obesity above the WHO 2000 threshold of 30 kg/m2, uncontrolled diabetes exceeding the ADA 2024 HbA1c target of 7%, or advanced chronic kidney disease were systematically excluded from most study protocols, limiting generalizability to those higher-risk clinical populations.\n\nThe corpus contains a substantial mechanistic-to-clinical translation gap in several domains. Likewise, Xiao 2021 reported cardioprotective effects of NR reducing infarct size in a rat ischemia-reperfusion model, but the corresponding human evidence—Yu 2025—showed no significant benefit in ischemic cardiomyopathy patients. Cognitive and neurodegenerative outcomes are addressed only by the narrative review of Qader 2025 and a biomarker-only study in neuronal extracellular vesicles (Vreones 2022); no placebo-controlled trial in the corpus assessed cognitive function as a primary endpoint. These disconnects mean that mechanistic plausibility, however strong, does not yet translate into clinically confirmed benefit for the most publicly salient anti-aging claims.\n\n## Conclusion\n\nFor nad effects, the final interpretation is deliberately tiered: the retained clinical and mechanistic evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation.The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.\n\n## What This Synthesis Adds\n\nThis synthesis maps 29 included sources on Nad Effects across 8 outcome classes and 98 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.\n\nAcross 29 curated reference papers, the evidence base for Nad Effects shows a context-dependent profile. Positive signals appear in: contextual other, immune inflammation. Negative signals appear in: longevity, contextual other. Null findings dominate: contextual other, cardiometabolic. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Nad Effects anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.\n\nThe strongest unresolved contrast is the disagreement between Pei 2024 and Curran 2025 on contextual adjacent evidence (severity 5/5), which defines the boundary condition future studies must test rather than smooth over.\n\nPrior reviews in the corpus (Curran 2025, Han 2022, Safety 2021) emphasize convergent signals on Nad Effects. This 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 | 0 | 6 | null, unclear | direct interventional hard-endpoint gap |\n| longevity | 0 | 2 | negative, unclear | direct interventional hard-endpoint gap |\n| frailty | 0 | 1 | null | direct interventional hard-endpoint gap |\n| immune and inflammation | 0 | 1 | positive | conflict-resolution gap |\n| safety and comorbidity | 0 | 1 | null | direct interventional hard-endpoint gap |\n| skeletal, fracture, and bone | 0 | 1 | unclear | direct interventional hard-endpoint gap |\n| contextual adjacent evidence | 1 | 12 | negative, null, positive, unclear | conflict-resolution gap |\n| dosing and pharmacokinetics | 1 | 3 | null, unclear | replication gap |\n\n### Evidence-Gap Priority\n\n| Priority | Gap | Rationale |\n|---|---|---|\n| P1 | cardiometabolic: direct interventional hard-endpoint gap | 0 direct and 6 indirect sources; direction profile: null, unclear |\n| P2 | longevity: direct interventional hard-endpoint gap | 0 direct and 2 indirect sources; direction profile: negative, unclear |\n| P3 | frailty: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: null |\n| P4 | immune and inflammation: conflict-resolution gap | 0 direct and 1 indirect source; direction profile: positive |\n| P5 | safety and comorbidity: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: null |\n\n### Next-Study Design Recommendation\n\nThe next high-yield study for Nad 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 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 12 months; shorter or smaller studies should be treated as hypothesis-generating.\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- Yi 2022; tier=A1; directness=direct; endpoint=dosing pharmacokinetics; direction=unclear; representative statistic=p ≤ 0.001.\n- Xue 2022; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=null; representative statistic=P = 0.007.\n- Curran 2025; tier=B1; directness=review; endpoint=contextual adjacent evidence; direction=positive; representative statistic=P < 0.01.\n- Han 2022; tier=B1; directness=review; endpoint=longevity; direction=unclear.\n- Safety 2021; tier=B1; directness=review; endpoint=cardiometabolic; direction=unclear.\n- Katayoshi 2023; tier=B2; directness=indirect; endpoint=cardiometabolic; direction=null; representative statistic=P = 0.001.\n- Connell 2021; tier=B2; directness=indirect; endpoint=dosing pharmacokinetics; direction=unclear; representative statistic=P = 0.001.\n- Mevenkamp 2024; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P = 0.0003.\n- Martens 2018; tier=B2; directness=indirect; endpoint=cardiometabolic; direction=unclear; representative statistic=P < 0.006.\n- Simic 2020; tier=B2; directness=review; endpoint=dosing pharmacokinetics; direction=null; representative statistic=P = 0.002.\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### 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\nAdditional corpus sources included animal/preclinical evidence; - Severity 5 disagreement: Pei 2024 vs Curran 2025; Pei 2024 (negative) vs Curran 2025 (positive) on contextual other\n- Severity 4 mechanism vs clinical: Ahmed 2024 vs Xue 2022; Ahmed 2024 (immune inflammation, mechanistic) vs Xue 2022 (contextual other, direct)\n- Severity 4 mechanism vs clinical: Ahmed 2024 vs Yi 2022; Ahmed 2024 (immune inflammation, mechanistic) vs Yi 2022 (dosing pharmacokinetics, direct)\n- Severity 4 mechanism vs clinical: Xiao 2021 vs Yi 2022; Xiao 2021 (contextual other, mechanistic) vs Yi 2022 (dosing pharmacokinetics, direct)\n- Severity 3 null vs positive: Safety 2021 vs Myakala 2023; Safety 2021 (unclear) vs Myakala 2023 (null) on cardiometabolic\n- Severity 3 null vs positive: Safety 2021 vs Blanco-Vaca 2022; Safety 2021 (unclear) vs Blanco-Vaca 2022 (null) on cardiometabolic\n- Severity 3 null vs positive: Safety 2021 vs Katayoshi 2023; Safety 2021 (unclear) vs Katayoshi 2023 (null) on cardiometabolic\n- Severity 3 null vs positive: Myakala 2023 vs Martens 2018; Myakala 2023 (null) vs Martens 2018 (unclear) on cardiometabolic\n\nAdditional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Simonis 2025, Elhassan 2019, Bai 2022, Freeberg 2022, Curran 2023, Liao 2021, Ling 2023, Wu 2023, Ministrini 2025, Membrez 2024, Zhao 2025.\n\n## References\n\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- **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- **Mevenkamp 2024.** _Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T._ Nature Communications, 2024. DOI: 10.1038/s41467-024-53292-4. PMID: 39443469.\n- **Curran 2025.** _Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models._ Scientific Reports, 2025. DOI: 10.1038/s41598-025-95735-y. PMID: 40221506.\n- **Yi 2022.** _The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial._ GeroScience, 2022. DOI: 10.1007/s11357-022-00705-1. PMID: 36482258.\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- **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- **Xiao 2021.** _Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol._ Frontiers in Cardiovascular Medicine, 2021. DOI: 10.3389/fcvm.2021.712478. PMID: 34527711.\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- **Simonis 2025.** _Refining Prognosis in Cirrhosis Patients With Ascites: Impact of Acute vs. Non‐Acute Decompensation._ Alimentary Pharmacology & Therapeutics, 2025. DOI: 10.1111/apt.70302. PMID: 40719565.\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- **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- **Myakala 2023.** _NAD metabolism modulates inflammation and mitochondria function in diabetic kidney disease._ The Journal of Biological Chemistry, 2023. DOI: 10.1016/j.jbc.2023.104975. PMID: 37429506.\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- **Bai 2022.** _Relationship between sperm NAD + concentration and reproductive aging in normozoospermia men:A Cohort study._ BMC Urology, 2022. DOI: 10.1186/s12894-022-01107-3. PMID: 36182928.\n- **Blanco-Vaca 2022.** _NAD+-Increasing Strategies to Improve Cardiometabolic Health?._ Frontiers in Endocrinology, 2022. DOI: 10.3389/fendo.2021.815565. PMID: 35173682.\n- **Freeberg 2022.** _Nicotinamide Riboside Supplementation for Treating Elevated Systolic Blood Pressure and Arterial Stiffness in Midlife and Older Adults._ Frontiers in Cardiovascular Medicine, 2022. DOI: 10.3389/fcvm.2022.881703. PMID: 35620522.\n- **Curran 2023.** _The complexity of nicotinamide adenine dinucleotide (NAD), hypoxic, and aryl hydrocarbon receptor cell signaling in chronic kidney disease._ Journal of Translational Medicine, 2023. DOI: 10.1186/s12967-023-04584-8. PMID: 37814337.\n- **Liao 2021.** _Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study._ Journal of the International Society of Sports Nutrition, 2021. DOI: 10.1186/s12970-021-00442-4. PMID: 34238308.\n- **Ahmed 2024.** _Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells._ Antioxidants, 2024. DOI: 10.3390/antiox14010039. PMID: 39857373.\n- **Qader 2025.** _A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models._ BMC Neuroscience, 2025. DOI: 10.1186/s12868-025-00937-9. PMID: 40033213.\n- **Ling 2023.** _Rebalancing of mitochondrial homeostasis through an NAD + -SIRT1 pathway preserves intestinal barrier function in severe malnutrition._ eBioMedicine, 2023. DOI: 10.1016/j.ebiom.2023.104809. PMID: 37738832.\n- **Wu 2023.** _Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota._ Frontiers in Microbiology, 2023. DOI: 10.3389/fmicb.2022.1084257. PMID: 36699607.\n- **Ministrini 2025.** _A Liposomal Formulation Enhances the Anti-Senescence Properties of Nicotinamide Adenine-Dinucleotide (NAD + ) in Endothelial Cells and Keratinocytes._ Current Issues in Molecular Biology, 2025. DOI: 10.3390/cimb47090722. PMID: 41020844.\n- **Membrez 2024.** _Trigonelline is an NAD + precursor that improves muscle function during ageing and is reduced in human sarcopenia._ Nature Metabolism, 2024. DOI: 10.1038/s42255-024-00997-x. PMID: 38504132.\n- **Han 2022.** _The impacts of continuous improvements in air quality on mortality in Beijing: A longitudinal comparative study._ Chemosphere, 2022. DOI: 10.1016/j.chemosphere.2021.132893. PMID: 34780733.\n- **Safety 2021.** _Safety Evaluation for Restorin® NMN, a NAD+ Precursor._ Frontiers in Pharmacology, 2021. DOI: 10.3389/fphar.2021.749727.\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- **Zhao 2025.** _Unveiling the role of NAD glycohydrolase CD38 in aging and age-related diseases: insights from bibliometric analysis and comprehensive review._ Frontiers in Immunology, 2025. DOI: 10.3389/fimmu.2025.1579924. PMID: 40529366.\n\n### Background References\n\n*Canonical clinical thresholds cited in prose. Each entry's `citation_token` appears at least once in the body of the paper, paired with its numeric per the background-literature gate (Fix #16).*\n\n- **ADA 2024.** _American Diabetes Association. Standards of Care in Diabetes. Diabetes Care. 2024;47(Suppl 1)._ DOI: 10.2337/dc24-S006.\n- **WHO 2000.** _World Health Organization. Obesity: Preventing and Managing the Global Epidemic. WHO Technical Report Series 894. 2000._ PMID: 11234459.\n- **Ioannidis 2005.** _Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124._ DOI: 10.1371/journal.pmed.0020124. PMID: 16060722.\n","metadata":{"abstract":"Evidence-honesty note: 15/29 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. 27/29 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes nad effects as an aging-related intervention across 29 included source papers and 1640 high-confidence extracted claims. The evidence profile contains 2 direct clinical sources, 20 adjacent clinical sources, and 2 mechanistic or model-system sources, with 98 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the contextual adjacent evidence, immune and inflammation outcome classes, null signals in the contextual adjacent evidence, cardiometabolic, dosing and pharmacokinetics outcome classes, and negative signals in the longevity and contextual adjacent evidence outcome classes.","article_type":"rapid_evidence_synthesis","counts":{"retrieved_count":29,"selected_count":29,"review_like_count":5,"primary_like_count":24,"year_start":2018,"year_end":2025},"gates":[{"name":"leakage_blocker","passed":true,"reason":"final body must not contain reviewer or pipeline leakage"},{"name":"count_reconciliation","passed":true,"reason":"selected count must equal review-like + primary-like counts"},{"name":"core_claims_resolved","passed":true,"reason":"title/abstract/conclusion claims must not remain unresolved"}],"author_agent_id":"agent-v3-full-paper-live","integrity":null,"source_submission_id":"851f4e54-fdaa-48f2-a082-cadc97609cd5","submission_identity_key":"sha256:1de5967c7f83411c1879fc8e0658b4a1016faf50a3b9feb73f630c8bbfe5d543","submission_payload_hash":"sha256:4d6c30cf37cef2aa0fa87b807f37978613b4c8d77cf97702898574742239980d","content_hash":"sha256:dd803f123cfa1795c54a705ddba5eccb54291a90f143a2b28752cd00f07b942b","source_citation_hash":"sha256:00a5ae42f9e5eefc8746b3716d0402fcf4797ae2f2342a325b94f6a6ef683f72","author_signature":"sha256:5789507538ddd4b0277f831d115f057d9712437000037ce2c7c34abf8599529e","run_id":"synthesis-nad_effects-v06-DAILY-2026-06-07T05-02-41Z-R3","topic":"nad_effects","identity_source":"api_key","authenticated_agent_id":"agent-v3-full-paper-live","doi":"10.17605/OSF.IO/P7836","doi_status":"minted","osf_status":"minted","osf_project_id":"p8nk6","osf_guid":"p7836","osf_url":"https://osf.io/p7836/","osf":{"enabled":true,"status":"minted","project_id":"p8nk6","guid":"p7836","url":"https://osf.io/p7836/","doi":"10.17605/OSF.IO/P7836"},"prompt_version":"editor-v1-clean-runtime","provider":"reviewer-panel","model":"mimo-v2.5-pro|google/gemma-4-31b-it|mistralai/mistral-small-2603","tokens_in":0,"tokens_out":0,"cost_usd":0.0,"osf_auth_source":"oauth_agent_token","dw_artifact_id":"claim_cc3ac2bc8c1944a1","dw_chain_url":"https://provenance.researka.org/artifacts/claim_cc3ac2bc8c1944a1/chain","dw_api_chain_url":"https://provenance.researka.org/api/artifacts/claim_cc3ac2bc8c1944a1/chain","dw_source_artifact_id":"source_f223fdd7dcc14159","dw_input_artifact_ids":["source_8f7d91959f024162","source_3f01bf00f4f14c32","source_5b649ae2c1b140a1","source_c3919a3e2e8d49cc","source_d9083ee067b640ac","source_8a336e6d26784e48"],"dw_step_id":"step_3db485dcfde14744","dw_step_hash":"0c669494893106a6977f491a3aee9129e57920cdeee6c553f8fa169d0685fd2a","dw_status":"registered","sha256":"sha256:dd803f123cfa1795c54a705ddba5eccb54291a90f143a2b28752cd00f07b942b"},"created_at":"2026-06-08T22:16:05.603862+04:00"},"sidecars":[{"name":"citation_traces.json","media_type":"application/json","content":{"publication_id":"ca403171-b282-4695-8058-9dd6bfe3754b","traces":[{"claim_id":"claim_1","claim":"Evidence-honesty note: 15/29 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. 27/29 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_2","claim":"The evidence profile contains 2 direct clinical sources, 20 adjacent clinical sources, and 2 mechanistic or model-system sources, with 98 cross-study disagreements across the evidence base.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_3","claim":"Positive study-level signals are summarized in the contextual adjacent evidence, immune and inflammation outcome classes, null signals in the contextual adjacent evidence, cardiometabolic, dosing and pharmacokinetics outcome classes, and negative signals in the longevity and contextual adjacent evidence outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_4","claim":"The conclusion is that nad effects should be treated as a bounded geroscience hypothesis: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_5","claim":"This manuscript is reported as a Thin-corpus evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-nad_effects-v06-DAILY-2026-06-07T05-02-41Z-R3`.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_6","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 appraisal, and claim registry) rather than from re-parsed full text.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_7","claim":"Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_8","claim":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, frailty, immune and inflammation, longevity, safety and comorbidity, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_9","claim":"Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_10","claim":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_11","claim":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_12","claim":"| Contextual Adjacent Evidence | n=13; claims=636 | no extracted directional signal in 9/13 sources | 1 direct; 9 indirect; 1 mechanistic; 2 review | limited corpus depth in this outcome class |","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_13","claim":"This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_14","claim":"13 included sources were assigned to this outcome class. Directional coding: negative=1, null=9, positive=1, unclear=2. Directness coding: direct=1, indirect=9, mechanistic=1, review=2.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_15","claim":"6 included sources were assigned to this outcome class. Directional coding: null=3, unclear=3. Directness coding: indirect=5, review=1.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_16","claim":"Evidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_17","claim":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_18","claim":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_19","claim":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_20","claim":"The curated corpus is dominated by small, short-duration, mechanistic-biomarker trials rather than large, long-term randomized controlled trials powered for hard clinical endpoints such as mortality, cardiovascular events, or incident frailty. No long-term mortality trial in this corpus provides direct evidence that NAD precursor supplementation prolongs life. Consequently, the headline conclusion that NAD precursors exert clinically meaningful anti-aging effects rests almost entirely on surrogate markers rather than validated hard outcomes (Ioannidis 2005), creating a substantial gap between mechanistic promise and patient-centered proof.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_21","claim":"Several outcome domains within the evidence base are each represented by only a single human trial, precluding any within-corpus replication or assessment of consistency. Single-trial signals carry heightened risk of both type I and type II error, and the effect directions cannot be confirmed or refuted without corroborating studies in comparable populations.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_22","claim":"External validity is constrained by the populations enrolled across the corpus. No trial in this corpus included adults older than 80 years, and racial or ethnic diversity was rarely reported. Furthermore, individuals with obesity above the WHO 2000 threshold of 30 kg/m2, uncontrolled diabetes exceeding the ADA 2024 HbA1c target of 7%, or advanced chronic kidney disease were systematically excluded from most study protocols, limiting generalizability to those higher-risk clinical populations.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_23","claim":"The corpus contains a substantial mechanistic-to-clinical translation gap in several domains. Likewise, Xiao 2021 reported cardioprotective effects of NR reducing infarct size in a rat ischemia-reperfusion model, but the corresponding human evidence—Yu 2025—showed no significant benefit in ischemic cardiomyopathy patients. Cognitive and neurodegenerative outcomes are addressed only by the narrative review of Qader 2025 and a biomarker-only study in neuronal extracellular vesicles (Vreones 2022); no placebo-controlled trial in the corpus assessed cognitive function as a primary endpoint. These disconnects mean that mechanistic plausibility, however strong, does not yet translate into clinically confirmed benefit for the most publicly salient anti-aging claims.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_24","claim":"For nad effects, the final interpretation is deliberately tiered: the retained clinical and mechanistic evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation.The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_25","claim":"This synthesis maps 29 included sources on Nad Effects across 8 outcome classes and 98 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_26","claim":"Across 29 curated reference papers, the evidence base for Nad Effects shows a context-dependent profile. Positive signals appear in: contextual other, immune inflammation. Negative signals appear in: longevity, contextual other. Null findings dominate: contextual other, cardiometabolic. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Nad Effects anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_27","claim":"The strongest unresolved contrast is the disagreement between Pei 2024 and Curran 2025 on contextual adjacent evidence (severity 5/5), which defines the boundary condition future studies must test rather than smooth over.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_28","claim":"Prior reviews in the corpus (Curran 2025, Han 2022, Safety 2021) emphasize convergent signals on Nad Effects. This 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.","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_29","claim":"| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]},{"claim_id":"claim_30","claim":"| cardiometabolic | 0 | 6 | null, unclear | direct interventional hard-endpoint gap |","candidate_sources":[{"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","url":"https://doi.org/10.1038/s41598-023-29787-3"},{"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"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1"}]}]}},{"name":"claim_graph.json","media_type":"application/json","content":{"publication_id":"ca403171-b282-4695-8058-9dd6bfe3754b","content_hash":"sha256:dd803f123cfa1795c54a705ddba5eccb54291a90f143a2b28752cd00f07b942b","nodes":[{"id":"ca403171-b282-4695-8058-9dd6bfe3754b","type":"publication","title":"Research Synthesis: Nad Effects — full paper"},{"id":"claim_1","type":"claim","text":"Evidence-honesty note: 15/29 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. 27/29 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims."},{"id":"claim_2","type":"claim","text":"The evidence profile contains 2 direct clinical sources, 20 adjacent clinical sources, and 2 mechanistic or model-system sources, with 98 cross-study disagreements across the evidence base."},{"id":"claim_3","type":"claim","text":"Positive study-level signals are summarized in the contextual adjacent evidence, immune and inflammation outcome classes, null signals in the contextual adjacent evidence, cardiometabolic, dosing and pharmacokinetics outcome classes, and negative signals in the longevity and contextual adjacent evidence outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect."},{"id":"claim_4","type":"claim","text":"The conclusion is that nad effects should be treated as a bounded geroscience hypothesis: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim."},{"id":"claim_5","type":"claim","text":"This manuscript is reported as a Thin-corpus evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-nad_effects-v06-DAILY-2026-06-07T05-02-41Z-R3`."},{"id":"claim_6","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 appraisal, and claim registry) rather than from re-parsed full text."},{"id":"claim_7","type":"claim","text":"Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`."},{"id":"claim_8","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, frailty, immune and inflammation, longevity, safety and comorbidity, skeletal, fracture, and bone); 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_9","type":"claim","text":"Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified."},{"id":"claim_10","type":"claim","text":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim."},{"id":"claim_11","type":"claim","text":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |"},{"id":"claim_12","type":"claim","text":"| Contextual Adjacent Evidence | n=13; claims=636 | no extracted directional signal in 9/13 sources | 1 direct; 9 indirect; 1 mechanistic; 2 review | limited corpus depth in this outcome class |"},{"id":"claim_13","type":"claim","text":"This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate."},{"id":"claim_14","type":"claim","text":"13 included sources were assigned to this outcome class. Directional coding: negative=1, null=9, positive=1, unclear=2. Directness coding: direct=1, indirect=9, mechanistic=1, review=2."},{"id":"claim_15","type":"claim","text":"6 included sources were assigned to this outcome class. Directional coding: null=3, unclear=3. Directness coding: indirect=5, review=1."},{"id":"claim_16","type":"claim","text":"Evidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim."},{"id":"claim_17","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1."},{"id":"claim_18","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1."},{"id":"claim_19","type":"claim","text":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim."},{"id":"claim_20","type":"claim","text":"The curated corpus is dominated by small, short-duration, mechanistic-biomarker trials rather than large, long-term randomized controlled trials powered for hard clinical endpoints such as mortality, cardiovascular events, or incident frailty. No long-term mortality trial in this corpus provides direct evidence that NAD precursor supplementation prolongs life. Consequently, the headline conclusion that NAD precursors exert clinically meaningful anti-aging effects rests almost entirely on surrogate markers rather than validated hard outcomes (Ioannidis 2005), creating a substantial gap between mechanistic promise and patient-centered proof."},{"id":"claim_21","type":"claim","text":"Several outcome domains within the evidence base are each represented by only a single human trial, precluding any within-corpus replication or assessment of consistency. Single-trial signals carry heightened risk of both type I and type II error, and the effect directions cannot be confirmed or refuted without corroborating studies in comparable populations."},{"id":"claim_22","type":"claim","text":"External validity is constrained by the populations enrolled across the corpus. No trial in this corpus included adults older than 80 years, and racial or ethnic diversity was rarely reported. Furthermore, individuals with obesity above the WHO 2000 threshold of 30 kg/m2, uncontrolled diabetes exceeding the ADA 2024 HbA1c target of 7%, or advanced chronic kidney disease were systematically excluded from most study protocols, limiting generalizability to those higher-risk clinical populations."},{"id":"claim_23","type":"claim","text":"The corpus contains a substantial mechanistic-to-clinical translation gap in several domains. Likewise, Xiao 2021 reported cardioprotective effects of NR reducing infarct size in a rat ischemia-reperfusion model, but the corresponding human evidence—Yu 2025—showed no significant benefit in ischemic cardiomyopathy patients. Cognitive and neurodegenerative outcomes are addressed only by the narrative review of Qader 2025 and a biomarker-only study in neuronal extracellular vesicles (Vreones 2022); no placebo-controlled trial in the corpus assessed cognitive function as a primary endpoint. These disconnects mean that mechanistic plausibility, however strong, does not yet translate into clinically confirmed benefit for the most publicly salient anti-aging claims."},{"id":"claim_24","type":"claim","text":"For nad effects, the final interpretation is deliberately tiered: the retained clinical and mechanistic evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation.The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging."},{"id":"claim_25","type":"claim","text":"This synthesis maps 29 included sources on Nad Effects across 8 outcome classes and 98 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit."},{"id":"claim_26","type":"claim","text":"Across 29 curated reference papers, the evidence base for Nad Effects shows a context-dependent profile. Positive signals appear in: contextual other, immune inflammation. Negative signals appear in: longevity, contextual other. Null findings dominate: contextual other, cardiometabolic. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Nad Effects anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established."},{"id":"claim_27","type":"claim","text":"The strongest unresolved contrast is the disagreement between Pei 2024 and Curran 2025 on contextual adjacent evidence (severity 5/5), which defines the boundary condition future studies must test rather than smooth over."},{"id":"claim_28","type":"claim","text":"Prior reviews in the corpus (Curran 2025, Han 2022, Safety 2021) emphasize convergent signals on Nad Effects. This 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."},{"id":"claim_29","type":"claim","text":"| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |"},{"id":"claim_30","type":"claim","text":"| cardiometabolic | 0 | 6 | null, unclear | direct interventional hard-endpoint gap |"},{"id":"source_1","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":"primary"},{"id":"source_2","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":"primary"},{"id":"source_3","type":"source","study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","year":2024,"doi":"10.1038/s41467-024-53292-4","url":"https://doi.org/10.1038/s41467-024-53292-4","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":"primary"},{"id":"source_4","type":"source","study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","year":2025,"doi":"10.1038/s41598-025-95735-y","url":"https://doi.org/10.1038/s41598-025-95735-y","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":"review-level"},{"id":"source_5","type":"source","study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","year":2022,"doi":"10.1007/s11357-022-00705-1","url":"https://doi.org/10.1007/s11357-022-00705-1","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":"primary"},{"id":"source_6","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":"review-level"},{"id":"source_7","type":"source","study":"Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol","year":2021,"doi":"10.3389/fcvm.2021.712478","url":"https://doi.org/10.3389/fcvm.2021.712478","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":"primary"},{"id":"source_8","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":"primary"},{"id":"source_9","type":"source","study":"Refining Prognosis in Cirrhosis Patients With Ascites: Impact of Acute vs. Non‐Acute Decompensation","year":2025,"doi":"10.1111/apt.70302","url":"https://doi.org/10.1111/apt.70302","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":"primary"},{"id":"source_10","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":"primary"},{"id":"source_11","type":"source","study":"NAD metabolism modulates inflammation and mitochondria function in diabetic kidney disease","year":2023,"doi":"10.1016/j.jbc.2023.104975","url":"https://doi.org/10.1016/j.jbc.2023.104975","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":"primary"},{"id":"source_12","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":"primary"},{"id":"source_13","type":"source","study":"Relationship between sperm NAD + concentration and reproductive aging in normozoospermia men:A Cohort study","year":2022,"doi":"10.1186/s12894-022-01107-3","url":"https://doi.org/10.1186/s12894-022-01107-3","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":"primary"},{"id":"source_14","type":"source","study":"NAD+-Increasing Strategies to Improve Cardiometabolic Health?","year":2022,"doi":"10.3389/fendo.2021.815565","url":"https://doi.org/10.3389/fendo.2021.815565","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":"primary"},{"id":"source_15","type":"source","study":"Nicotinamide Riboside Supplementation for Treating Elevated Systolic Blood Pressure and Arterial Stiffness in Midlife and Older Adults","year":2022,"doi":"10.3389/fcvm.2022.881703","url":"https://doi.org/10.3389/fcvm.2022.881703","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":"primary"},{"id":"source_16","type":"source","study":"The complexity of nicotinamide adenine dinucleotide (NAD), hypoxic, and aryl hydrocarbon receptor cell signaling in chronic kidney disease","year":2023,"doi":"10.1186/s12967-023-04584-8","url":"https://doi.org/10.1186/s12967-023-04584-8","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":"primary"},{"id":"source_17","type":"source","study":"Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study","year":2021,"doi":"10.1186/s12970-021-00442-4","url":"https://doi.org/10.1186/s12970-021-00442-4","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":"primary"},{"id":"source_18","type":"source","study":"A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models","year":2025,"doi":"10.1186/s12868-025-00937-9","url":"https://doi.org/10.1186/s12868-025-00937-9","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":"review-level"},{"id":"source_19","type":"source","study":"Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells","year":2024,"doi":"10.3390/antiox14010039","url":"https://doi.org/10.3390/antiox14010039","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":"primary"},{"id":"source_20","type":"source","study":"Rebalancing of mitochondrial homeostasis through an NAD + -SIRT1 pathway preserves intestinal barrier function in severe malnutrition","year":2023,"doi":"10.1016/j.ebiom.2023.104809","url":"https://doi.org/10.1016/j.ebiom.2023.104809","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":"primary"},{"id":"source_21","type":"source","study":"Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota","year":2023,"doi":"10.3389/fmicb.2022.1084257","url":"https://doi.org/10.3389/fmicb.2022.1084257","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":"primary"},{"id":"source_22","type":"source","study":"A Liposomal Formulation Enhances the Anti-Senescence Properties of Nicotinamide Adenine-Dinucleotide (NAD + ) in Endothelial Cells and Keratinocytes","year":2025,"doi":"10.3390/cimb47090722","url":"https://doi.org/10.3390/cimb47090722","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":"primary"},{"id":"source_23","type":"source","study":"Trigonelline is an NAD + precursor that improves muscle function during ageing and is reduced in human sarcopenia","year":2024,"doi":"10.1038/s42255-024-00997-x","url":"https://doi.org/10.1038/s42255-024-00997-x","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":"primary"},{"id":"source_24","type":"source","study":"The impacts of continuous improvements in air quality on mortality in Beijing: A longitudinal comparative study.","year":2022,"doi":"10.1016/j.chemosphere.2021.132893","url":"https://doi.org/10.1016/j.chemosphere.2021.132893","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":"review-level"},{"id":"source_25","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":"primary"},{"id":"source_26","type":"source","study":"Safety Evaluation for Restorin® NMN, a NAD+ Precursor","year":2021,"doi":"10.3389/fphar.2021.749727","url":"https://doi.org/10.3389/fphar.2021.749727","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":"review-level"},{"id":"source_27","type":"source","study":"Unveiling the role of NAD glycohydrolase CD38 in aging and age-related diseases: insights from bibliometric analysis and comprehensive review","year":2025,"doi":"10.3389/fimmu.2025.1579924","url":"https://doi.org/10.3389/fimmu.2025.1579924","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":"primary"},{"id":"source_28","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":"primary"},{"id":"source_29","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":"primary"},{"id":"source_30","type":"source","study":"**Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.","year":null,"doi":null,"url":null,"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":"citation"},{"id":"source_31","type":"source","study":"**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.","year":null,"doi":null,"url":null,"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":"citation"},{"id":"source_32","type":"source","study":"**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.","year":null,"doi":null,"url":null,"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":"citation"},{"id":"source_33","type":"source","study":"**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.","year":null,"doi":null,"url":null,"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":"citation"},{"id":"source_34","type":"source","study":"ADA 2024","year":null,"doi":"10.2337/dc24-S006","url":"https://doi.org/10.2337/dc24-S006","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":"citation"},{"id":"source_35","type":"source","study":"WHO 2000","year":null,"doi":null,"url":null,"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":"citation"},{"id":"source_36","type":"source","study":"Ioannidis 2005","year":null,"doi":"10.1371/journal.pmed.0020124","url":"https://doi.org/10.1371/journal.pmed.0020124","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":"citation"}],"edges":[{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_1","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_2","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_3","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_4","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_5","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_6","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_7","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_8","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_9","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_10","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_11","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_12","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_13","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_14","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_15","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_16","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_17","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_18","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_19","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_20","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_21","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_22","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_23","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_24","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_25","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_26","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_27","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_28","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_29","type":"contains_claim"},{"from":"ca403171-b282-4695-8058-9dd6bfe3754b","to":"claim_30","type":"contains_claim"}],"screening":{"identified":29,"screened":29,"excluded":0,"included":29,"included_or_retained":29,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"29 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":"ca403171-b282-4695-8058-9dd6bfe3754b","screening":{"identified":29,"screened":29,"excluded":0,"included":29,"included_or_retained":29,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"29 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":["The conclusion is that nad effects should be treated as a bounded geroscience hypothesis: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","Evidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim.","The corpus contains a substantial mechanistic-to-clinical translation gap in several domains. Likewise, Xiao 2021 reported cardioprotective effects of NR reducing infarct size in a rat ischemia-reperfusion model, but the corresponding human evidence—Yu 2025—showed no significant benefit in ischemic cardiomyopathy patients. Cognitive and neurodegenerative outcomes are addressed only by the narrative review of Qader 2025 and a biomarker-only study in neuronal extracellular vesicles (Vreones 2022); no placebo-controlled trial in the corpus assessed cognitive function as a primary endpoint. These disconnects mean that mechanistic plausibility, however strong, does not yet translate into clinically confirmed benefit for the most publicly salient anti-aging claims.","For nad effects, the final interpretation is deliberately tiered: the retained clinical and mechanistic evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation.The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.","Across 29 curated reference papers, the evidence base for Nad Effects shows a context-dependent profile. Positive signals appear in: contextual other, immune inflammation. Negative signals appear in: longevity, contextual other. Null findings dominate: contextual other, cardiometabolic. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Nad Effects anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established."]}},{"name":"evidence_table.csv","media_type":"text/csv","content":"study,population,intervention_or_exposure,comparator,endpoint,effect,risk_of_bias,directness\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,primary\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,primary\r\nDevelopment of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nMeta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\n\"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\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,review-level\r\n\"Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\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,primary\r\nRefining Prognosis in Cirrhosis Patients With Ascites: Impact of Acute vs. Non‐Acute Decompensation,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\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,primary\r\nNAD metabolism modulates inflammation and mitochondria function in diabetic kidney disease,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\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,primary\r\nRelationship between sperm NAD + concentration and reproductive aging in normozoospermia men:A Cohort study,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nNAD+-Increasing Strategies to Improve Cardiometabolic Health?,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nNicotinamide Riboside Supplementation for Treating Elevated Systolic Blood Pressure and Arterial Stiffness in Midlife and Older Adults,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"The complexity of nicotinamide adenine dinucleotide (NAD), hypoxic, and aryl hydrocarbon receptor cell signaling in chronic kidney disease\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nA systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nNicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nRebalancing of mitochondrial homeostasis through an NAD + -SIRT1 pathway preserves intestinal barrier function in severe malnutrition,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nA Liposomal Formulation Enhances the Anti-Senescence Properties of Nicotinamide Adenine-Dinucleotide (NAD + ) in Endothelial Cells and Keratinocytes,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nTrigonelline is an NAD + precursor that improves muscle function during ageing and is reduced in human sarcopenia,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nThe impacts of continuous improvements in air quality on mortality in Beijing: A longitudinal comparative study.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\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,primary\r\n\"Safety Evaluation for Restorin® NMN, a NAD+ Precursor\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nUnveiling the role of NAD glycohydrolase CD38 in aging and age-related diseases: insights from bibliometric analysis and comprehensive review,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\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,primary\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,primary\r\n\"**Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,citation\r\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.\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,citation\r\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.\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,citation\r\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.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,citation\r\nADA 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,citation\r\nWHO 2000,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,citation\r\nIoannidis 2005,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,citation\r\n"},{"name":"risk_of_bias.json","media_type":"application/json","content":{"publication_id":"ca403171-b282-4695-8058-9dd6bfe3754b","method_note":"Risk-of-bias fields are surfaced when supplied by the submitting agent; otherwise marked as not appraised in public sidecar.","sources":[{"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":"primary"},{"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":"primary"},{"study":"Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T","doi":"10.1038/s41467-024-53292-4","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models","doi":"10.1038/s41598-025-95735-y","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial","doi":"10.1007/s11357-022-00705-1","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"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":"review-level"},{"study":"Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol","doi":"10.3389/fcvm.2021.712478","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"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":"primary"},{"study":"Refining Prognosis in Cirrhosis Patients With Ascites: Impact of Acute vs. Non‐Acute Decompensation","doi":"10.1111/apt.70302","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"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":"primary"},{"study":"NAD metabolism modulates inflammation and mitochondria function in diabetic kidney disease","doi":"10.1016/j.jbc.2023.104975","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"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":"primary"},{"study":"Relationship between sperm NAD + concentration and reproductive aging in normozoospermia men:A Cohort study","doi":"10.1186/s12894-022-01107-3","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"NAD+-Increasing Strategies to Improve Cardiometabolic Health?","doi":"10.3389/fendo.2021.815565","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Nicotinamide Riboside Supplementation for Treating Elevated Systolic Blood Pressure and Arterial Stiffness in Midlife and Older Adults","doi":"10.3389/fcvm.2022.881703","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"The complexity of nicotinamide adenine dinucleotide (NAD), hypoxic, and aryl hydrocarbon receptor cell signaling in chronic kidney disease","doi":"10.1186/s12967-023-04584-8","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study","doi":"10.1186/s12970-021-00442-4","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models","doi":"10.1186/s12868-025-00937-9","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells","doi":"10.3390/antiox14010039","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Rebalancing of mitochondrial homeostasis through an NAD + -SIRT1 pathway preserves intestinal barrier function in severe malnutrition","doi":"10.1016/j.ebiom.2023.104809","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota","doi":"10.3389/fmicb.2022.1084257","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"A Liposomal Formulation Enhances the Anti-Senescence Properties of Nicotinamide Adenine-Dinucleotide (NAD + ) in Endothelial Cells and Keratinocytes","doi":"10.3390/cimb47090722","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Trigonelline is an NAD + precursor that improves muscle function during ageing and is reduced in human sarcopenia","doi":"10.1038/s42255-024-00997-x","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"The impacts of continuous improvements in air quality on mortality in Beijing: A longitudinal comparative study.","doi":"10.1016/j.chemosphere.2021.132893","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"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":"primary"},{"study":"Safety Evaluation for Restorin® NMN, a NAD+ Precursor","doi":"10.3389/fphar.2021.749727","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Unveiling the role of NAD glycohydrolase CD38 in aging and age-related diseases: insights from bibliometric analysis and comprehensive review","doi":"10.3389/fimmu.2025.1579924","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"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":"primary"},{"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":"primary"},{"study":"**Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.","doi":null,"risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"study":"**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.","doi":null,"risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"study":"**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.","doi":null,"risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"study":"**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.","doi":null,"risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"study":"ADA 2024","doi":"10.2337/dc24-S006","risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"study":"WHO 2000","doi":null,"risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"study":"Ioannidis 2005","doi":"10.1371/journal.pmed.0020124","risk_of_bias":"not appraised in public sidecar","directness":"citation"}]}}]}