{"@context":"https://w3id.org/ro/crate/1.1/context","@type":"Dataset","id":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","name":"Hypothesis-Generating Brief: Spermidine supplementation — full paper","doi":"10.17605/OSF.IO/8SCDK","doi_status":"minted","osf_url":"https://osf.io/8scdk/","dw_chain_url":"https://provenance.researka.org/artifacts/claim_789460b431ab4a6d/chain","content_hash":"sha256:9556ccfe3729e54ceb5a9e50ab90961712fe6e73b90c4129bd617e0e015833cb","provenance_passport":{"publication_id":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","submission_id":"d3cc9fac-8c1a-4b6f-abe8-06b5d6cf0a22","artifact_type":"research_paper","decision":"accept","content_hash":"sha256:9556ccfe3729e54ceb5a9e50ab90961712fe6e73b90c4129bd617e0e015833cb","persistent_identifiers":{"doi":"10.17605/OSF.IO/8SCDK","osf_url":"https://osf.io/8scdk/","orcid":null,"ror_id":null,"raid_id":null},"persistent_identifier_status":{"doi":"supplied","osf_url":"supplied","orcid":"not_supplied","ror_id":"not_supplied","raid_id":"not_supplied"},"institution":{"name":null,"ror_id":null,"status":"not_supplied"},"integrity":{"recommendation":"unavailable","available":false,"matched_publication_id":null,"duplication_score":null,"similarity_score":null,"plagiarism_flag":false,"matched_sources":[],"breakdown":{},"feedback_for_agent":null,"status":"unavailable"},"provenance":{"dw_artifact_id":"claim_789460b431ab4a6d","dw_chain_url":"https://provenance.researka.org/artifacts/claim_789460b431ab4a6d/chain"},"timeline":["submission_intake","autonomous_review","autonomous_editorial_decision","autonomous_publish"]},"publication":{"id":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","object_type":"publication","parent_object_id":"d3cc9fac-8c1a-4b6f-abe8-06b5d6cf0a22","title":"Hypothesis-Generating Brief: Spermidine supplementation — full paper","body_markdown":"# Hypothesis-Generating Brief: Spermidine supplementation — full paper\n## Abstract\n\nEvidence-honesty note: 35/42 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. 37/42 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 evidence on Spermidine supplementation across 42 included source papers and 1250 high-confidence extracted claims.\n\nThe evidence profile contains 5 direct clinical sources, 33 adjacent clinical sources, and 4 mechanistic or model-system sources, with 206 cross-study disagreements across the evidence base.\n\nPositive study-level signals are summarized in the immune and inflammation outcome class; null signals are summarized in the contextual adjacent evidence, mechanism, dosing and pharmacokinetics, longevity, cardiometabolic, deficiency prevalence, muscle function, and skeletal, fracture, and bone outcome classes; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the safety and comorbidity and frailty 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 Spermidine supplementation 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-spermidine-v06-DAILY-2026-06-23T23-09-55Z-R2`.\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: 2026-06-23.\n\n### Search strategy\nThe following topic-anchored queries were executed against the information sources listed above:\n\n- `spermidine AND aging AND human`\n- `spermidine supplementation AND randomized trial`\n- `spermidine AND cognition AND older adults`\n- `dietary spermidine AND mortality AND cohort`\n- `spermidine AND autophagy AND aging`\n- `polyamine intake AND aging AND cohort`\n- `wheat germ extract AND spermidine AND trial`\n- `spermidine AND cardiometabolic AND human`\n- `spermidine-rich wheat germ AND memory AND older adults`\n- `SmartAge spermidine AND cognition`\n- (... 3 additional queries; see `methods_pack.json` for the full list)\n\n### Eligibility criteria\n- Sources whose primary content addresses spermidine.\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 1011 records in the receipt-candidate union, 987 were classified as source candidates and 42 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 | 1011 |\n| Classified source candidates | 987 |\n| No extractable claims | 38 |\n| None-only claim binding | 5 |\n| Mixed partial-or-none claim-binding candidates | 56 |\n| Partial-only claim-binding candidates | 12 |\n| Strict high-confidence sources | 9 |\n| Admitted final sources | 42 |\n\n### Exclusion reasons\n- No records were excluded at the gates instrumented for this run: the eligibility criteria above were applied during retrieval and claim-binding but produced no post-screening exclusions with recorded counts for this corpus.\n\n### Data items\nThe following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text.\n\n### Risk-of-bias appraisal\nRisk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.\n\n### Synthesis approach\nEvidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, dosing and pharmacokinetics, frailty, immune and inflammation, longevity, mechanism, muscle function, 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. Certification under the `researka_agent_certified` model verifies that the manuscript is machine-verifiable, internally consistent, provenance-traced, and format-checked against these artifacts; it does not adjudicate domain correctness, corpus fit, or novelty, which remain subject to expert and reader review.\n\n## Results\n| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |\n|---|---|---|---|---|\n| Contextual Adjacent Evidence | n=25; claims=671 | no extracted directional signal in 22/25 sources | 2 direct; 14 indirect; 1 protocol; 8 review | limited corpus depth in this outcome class |\n| Immune and Inflammation | n=3; claims=240 | positive signal in 2/3 sources | 1 direct; 2 indirect | limited corpus depth in this outcome class |\n| Mechanism | n=3; claims=29 | no extracted directional signal in 3/3 sources | 3 mechanistic | limited corpus depth in this outcome class |\n| Dosing and Pharmacokinetics | n=2; claims=77 | no extracted directional signal in 2/2 sources | 2 review | limited corpus depth in this outcome class |\n| Longevity | n=2; claims=37 | no extracted directional signal in 2/2 sources | 1 indirect; 1 review | limited corpus depth in this outcome class |\n| Safety and Comorbidity | n=2; claims=77 | unclear signal in 1/2 sources | 1 indirect; 1 mechanistic | limited corpus depth in this outcome class |\n| Cardiometabolic | n=1; claims=4 | no extracted directional signal in 1/1 sources | 1 direct | single-source slice; hypothesis-generating |\n| Deficiency Prevalence | n=1; claims=24 | no extracted directional signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n| Frailty | n=1; claims=75 | mixed signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n| Muscle Function | n=1; claims=11 | no extracted directional signal in 1/1 sources | 1 review | single-source slice; hypothesis-generating |\n| Skeletal, Fracture, and Bone | n=1; claims=5 | no extracted directional signal in 1/1 sources | 1 direct | single-source slice; hypothesis-generating |\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\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\n25 included sources were assigned to this outcome class. Directional coding: negative=1, null=22, unclear=2. Directness coding: direct=2, indirect=14, protocol=1, review=8.\n\n### Immune Inflammation Outcomes\n\n3 included sources were assigned to this outcome class. Directional coding: null=1, positive=2. Directness coding: direct=1, indirect=2.\n\n### Mechanism Outcomes\n\n3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: mechanistic=3.\n\n### Dosing Pharmacokinetics Outcomes\n\n2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: review=2.\n\n### Longevity Outcomes\n\n2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=1, review=1.\n\n### Safety Comorbidity Outcomes\n\n2 included sources were assigned to this outcome class. Directional coding: null=1, unclear=1. Directness coding: indirect=1, mechanistic=1.\n\n### Cardiometabolic Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: direct=1.\n\n### Deficiency Prevalence Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.\n\n### Frailty Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: mixed=1. Directness coding: indirect=1.\n\n### Muscle Function Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: review=1.\n\n### Skeletal Fracture Bone Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: direct=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\nAdditional corpus sources included animal/preclinical evidence; the corpus does not contain any large, long-term mortality or major cardiovascular event trial of spermidine in non-diabetic older adults, which is the canonical evidence type that would be required to support a hard-outcome claim in this population. With Schwarz 2022 reporting for the primary memory endpoint and Schwarz 2018 reporting P = 0.765 and P = 0.672 for tolerability comparisons in the Phase II cohort, the present corpus cannot anchor any conclusion about clinical events such as mortality, incident dementia, or myocardial infarction. The absence of such trials means the headline framing of a 'context-dependent profile' must be read as a statement about biomarkers, mechanistic readouts, and short-term functional proxies, not as an evidence-based claim about disease incidence or survival.\n\nSeveral outcome classes in the corpus rest on a single source and therefore cannot be replicated within the available evidence. Because no second source in the corpus tests the same endpoint with comparable design, these signals cannot be cross-validated internally, and any claim of reproducibility for them is unsupported.\n\nThe trials that were conducted enrolled narrow populations, which constrains external validity. No source in the corpus enrolled healthy young adults, children, pregnant women, or non-Caucasian populations as a primary focus. The Felix 2024 RCT, frequently cited as the strongest positive human signal, used a combination product containing AM3 (150 mg), spermidine (0.6 mg) and hesperidin, so its positive immune/inflammation findings (P < 0.01, P < 0.05, P < 0.001) cannot be attributed to spermidine monotherapy and the immune-inflammation positive signal in the synthesis is in part a combination-product signal rather than a spermidine-only effect.\n\nThe endpoint scope of the corpus is narrow and skewed toward mechanism, biomarker, and short-term proxy measures. The clinical/functional RCT class is represented by Keohane 2024 and Iorio-Siciliano 2024, both with non-significant primary endpoints, and by Felix 2024 with biomarker-level outcomes; no source in the corpus reports hard clinical events (mortality, incident frailty, incident dementia, fracture, hospitalization) as a randomised primary endpoint. Polyamine-level pharmacokinetics are addressed in Senekowitsch 2023 (high-dose supplementation did not increase plasma or salivary spermidine, P = 0.0282) and Keohane 2024, but dose-response, threshold, and target-tissue exposure remain underdetermined. Inferential shortcuts from biomarker to event are not licensed by the available evidence, consistent with the general methodological caution of Ioannidis 2005 that surrogate associations do not guarantee hard-outcome validity.\n\nSeveral clinically relevant claims in the corpus rest on mechanistic rather than clinical evidence. The Felix 2024 RCT, the only direct human RCT in the corpus on immune/inflammation, used a combination product (AM3 150 mg, spermidine 0.6 mg, hesperidin), so the apparent positive signal in that outcome class is shared between spermidine and co-administered bioactives; the second positive source, Trivedi 2026, is a Gulf War Illness mouse model and is therefore not a human clinical confirmation. Consequently the gap between mechanistic plausibility and clinic-ready evidence is the dominant limitation of the present corpus, and the 'context-dependent profile' described in the integrating thesis is supported as a statement about biomarkers and animal models, not as a statement about clinical benefit in human patients.\n\n## Conclusion\n\nAcross the 42 curated references assembled for this synthesis, the case for spermidine as a stand-alone geroprotective intervention appears to be, on balance, incomplete and context-dependent rather than settled. The strongest signal consistent with a benefit remains Felix 2024, the only direct human RCT in the immune-inflammation outcome class, in which a 150 mg AM3 / 0.6 mg spermidine / hesperidin blend produced statistically significant improvements (P < 0.01 to P < 0.001) in immune function and biological-age markers — but because spermidine was delivered as one component of a three-ingredient combination product, the trial cannot, in fairness, be used to attribute the effect to spermidine monotherapy. Taken together — one combination-product-positive trial, one preclinical-positive mouse model, one large-observational-negative study, and multiple direct human-RCT nulls — the evidence base appears to support a hypothesis that spermidine may contribute to immune and cognitive resilience in selected settings, but the hypothesis remains to be confirmed in adequately powered, monotherapy human trials with hard clinical endpoints, and any current off-label use as a geroprotective agent should remain pending further trials rather than being marketed or recommended as a proven standalone anti-aging intervention. The most urgent next step, in our reading, is a registered, placebo-controlled, dose-finding human RCT of pure spermidine — not combination products, not dietary intake surrogates — with pre-specified cognitive, frailty, and immune endpoints, so that the field can stop inferring geroprotection from indirect biomarkers, surrogate endpoints (Ioannidis 2005), and mouse models.\n\n## What This Synthesis Adds\n\nThis synthesis maps 42 included sources on Spermidine across 11 outcome classes and 206 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 42 curated reference papers, the evidence base for spermidine shows a context-dependent profile. Positive signals appear in immune inflammation; negative signals appear in contextual other; and null findings dominate contextual other and mechanism. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The spermidine 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 null vs negative between Effect of Foliar Application 2023 and He 2025 on contextual adjacent evidence (severity 4/5), which defines the boundary condition future studies must test rather than smooth over.\n\nThis synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.\n\n### Boundary-Condition Matrix\n\n| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |\n|---|---:|---:|---|---|\n| longevity | 0 | 2 | null | direct interventional hard-endpoint gap |\n| frailty | 0 | 1 | mixed | direct interventional hard-endpoint gap |\n| mechanism | 0 | 3 | null | direct interventional hard-endpoint gap |\n| muscle function | 0 | 1 | null | direct interventional hard-endpoint gap |\n| cardiometabolic | 1 | 0 | null | replication gap |\n| deficiency prevalence | 0 | 1 | null | direct interventional hard-endpoint gap |\n| dosing and pharmacokinetics | 0 | 2 | null | direct interventional hard-endpoint gap |\n| safety and comorbidity | 0 | 2 | null, unclear | direct interventional hard-endpoint gap |\n| contextual adjacent evidence | 2 | 23 | negative, null, unclear | conflict-resolution gap |\n| immune and inflammation | 1 | 2 | null, positive | conflict-resolution gap |\n| skeletal, fracture, and bone | 1 | 0 | null | replication gap |\n\n### Evidence-Gap Priority\n\n| Priority | Gap | Rationale |\n|---|---|---|\n| P1 | longevity: direct interventional hard-endpoint gap | 0 direct and 2 indirect sources; direction profile: null |\n| P2 | frailty: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: mixed |\n| P3 | mechanism: direct interventional hard-endpoint gap | 0 direct and 3 indirect sources; direction profile: null |\n| P4 | muscle function: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: null |\n| P5 | cardiometabolic: replication gap | 1 direct and 0 indirect source; direction profile: null |\n\n### Next-Study Design Recommendation\n\nThe next high-yield study for Spermidine should target the **longevity** 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## Tensions and Gaps\n\nEvidence-gap priority: The tension analysis separates claim-level disagreement counts from substantive cross-context evidence gaps. Biomarker-positive source-level findings are not pooled with mixed or null clinical-endpoint findings. The unresolved breadth therefore spans the reviewer-named adjacent contexts, and these contexts remain hypothesis-generating unless represented by retained direct clinical endpoint evidence. The manuscript reports 206 claim-level cross-study disagreements from the manifest; that number is a claim-level count, not an independently pooled source-pair count. Actually surfaced tensions include:\n- Trivedi 2026 vs Wet 2021: surfaced tension/disagreement in Immune and Inflammation because directions are positive versus null.\n- Trivedi 2026 vs Sanayama 2023: surfaced tension/disagreement in Immune and Inflammation because directions are positive versus mixed.\n- Trivedi 2026 vs Senekowitsch 2023: surfaced tension/disagreement in Immune and Inflammation because directions are positive versus null.\n\n## Evidence Snapshot\n\nSource directness breakdown: 5/42 retained sources directly address the stated topic and aging-relevant hard endpoints; 37/42 are adjacent, contextual, review-level, or mechanistic and are used only to bound interpretation. A qualifying direct source would directly test the named exposure or construct in the target population with aging-relevant clinical or hard-endpoint follow-up. Inclusion rationale: adjacent sources are reclassified as contextual rather than used for broad efficacy claims.\n\n### Source Outcome-Class Map\n\nRole-accounting note: retained translational or mechanistic-with-human-correlational evidence is mapped by its public outcome and directness row; preclinical or mechanistic records that are not retained in the source map are excluded from clinical outcome-class tallies.\n\nTension-accounting note: disagreement counts are claim-level. Substantive tension still remains between biomarker-elevating studies and mixed/null clinical-endpoint studies, so these contrasts are treated as unresolved evidence gaps.\n\n3 reviewer-named sources are not retained in this source map and are not counted in clinical outcome-class tallies unless listed below.\n\n- Wet 2021: Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Trivedi 2026: Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis: outcome=Immune and Inflammation; directness=indirect; tier=B2.\n\n- Sanayama 2023: Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults: outcome=Frailty; directness=indirect; tier=B2.\n\n- Senekowitsch 2023: High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study: outcome=Dosing and Pharmacokinetics; directness=review; tier=B2.\n\n- Alsaleh 2026: Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study: outcome=Immune and Inflammation; directness=indirect; tier=B2.\n\n- Thorup 2025: POLYamine treatment in elderly patients with Coronary Artery Disease (POLYCAD): study protocol for a Danish randomised, double-blind, placebo-controlled trial of spermidine treatment versus placebo: outcome=Contextual Adjacent Evidence; directness=protocol; tier=D1.\n\n- Mahajan 2020: Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Felix 2024: Human Supplementation with AM3, Spermidine, and Hesperidin Enhances Immune Function, Decreases Biological Age, and Improves Oxidative–Inflammatory State: A Randomized Controlled Trial: outcome=Immune and Inflammation; directness=direct; tier=A1.\n\n- Fischer 2020: Spermine and spermidine modulate T-cell function in older adults with and without cognitive decline ex vivo: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Schwarz 2018: Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline: outcome=Safety and Comorbidity; directness=mechanistic; tier=C1.\n\n- Schwarz 2022: Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Men 2025: Spermidine improves seed viability in Allium mongolicum by regulating AmCS-mediated metabolic and antioxidant networks: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Marcinska 2020: Exogenous Polyamines Only Indirectly Induce Stress Tolerance in Wheat Growing in Hydroponic Culture under Polyethylene Glycol-Induced Osmotic Stress: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Alsaleh 2020: Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Pekar 2020: The positive effect of spermidine in older adults suffering from dementia: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Nayak 2020: N8‐Acetylspermidine: A Polyamine Biomarker in Ischemic Cardiomyopathy With Reduced Ejection Fraction: outcome=Longevity; directness=indirect; tier=B2.\n\n- Wirth 2019: Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)—study protocol for a randomized controlled trial: outcome=Contextual Adjacent Evidence; directness=direct; tier=A1.\n\n- In animal/preclinical evidence, Sacitharan 2018: Spermidine restores dysregulated autophagy and polyamine synthesis in aged and osteoarthritic chondrocytes via EP300: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Yang 2024: Plasma Polyamines and Short‐Term Adverse Outcomes Among Patients With Ischemic Stroke: A Prospective Cohort Study: outcome=Safety and Comorbidity; directness=indirect; tier=B2.\n\n- Xu 2022: Non-linear association between serum spermidine and mild cognitive impairment: Results from a cross-sectional and longitudinal study: outcome=Deficiency Prevalence; directness=indirect; tier=B2.\n\n- Fredericks 2024: 5-ALA localises to the autophagy compartment and increases its fluorescence upon autophagy enhancement through caloric restriction and spermidine treatment in human glioblastoma: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Choi 2026: Functional and Biochemical Characterization of Spermidine Synthase CauSpe3 from Candidozyma auris: outcome=Mechanism; directness=mechanistic; tier=C1.\n\n- He 2025: High Plasma Polyamine Levels Are Associated With an Increased Risk of Poststroke Cognitive Impairment: A Multicenter Prospective Study From CATIS.: outcome=Contextual Adjacent Evidence; directness=review; tier=B2.\n\n- Zhang 2026: Targeting Polyamine Metabolism in Colorectal Cancer: Apigenin Dismantles the HIF-1α/SMOX Positive Feedback Loop to Suppress Tumor Progression: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Qi 2026: Spermidine improve high copper diet-induced intestinal oxidative stress and microbiota community composition.: outcome=Contextual Adjacent Evidence; directness=review; tier=B2.\n\n- In animal/preclinical evidence, Munoz-Esparza 2019: Polyamines in Food: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Yuan 2021: Spermidine induces cytoprotective autophagy of female germline stem cells in vitro and ameliorates aging caused by oxidative stress through upregulated sequestosome-1/p62 expression: outcome=Mechanism; directness=mechanistic; tier=C1.\n\n- Bruno 2025: Effects of Spermidine-Rich Rice Germ Extract Supplement on Biomarkers of Healthy Aging and Autophagy-Proof-of-Concept Pilot Study.: outcome=Contextual Adjacent Evidence; directness=review; tier=B2.\n\n- Thorup 2026: Spermidine and spermine in elderly patients with coronary artery disease: a cross-sectional study of dietary intake and plasma and skeletal muscle concentrations.: outcome=Muscle Function; directness=review; tier=B2.\n\n- Wirth 2018: The effect of spermidine on memory performance in older adults at risk for dementia: A randomized controlled trial.: outcome=Contextual Adjacent Evidence; directness=direct; tier=A1.\n\n- Iorio-Siciliano 2024: Treatment of peri-implant mucositis using spermidine and calcium chloride as local adjunctive delivery to non-surgical mechanical debridement: a double-blind randomized controlled clinical trial.: outcome=Skeletal, Fracture, and Bone; directness=direct; tier=A1.\n\n- Keohane 2024: Supplementation of spermidine at 40 mg/day has minimal effects on circulating polyamines: An exploratory double-blind randomized controlled trial in older men.: outcome=Cardiometabolic; directness=direct; tier=A1.\n\n- Autophagy-Enhancers to Reduce Sleep n.d.: Autophagy-Enhancers to Reduce Sleep Disturbances: outcome=Contextual Adjacent Evidence; directness=review; tier=B2.\n\n- SPERMIDINE TOXICITY in MITOCHONDRIAL 2022: SPERMIDINE TOXICITY IN MITOCHONDRIAL DNA-DEFICIENT SACCHAROMYCES CEREVISIAE: outcome=Longevity; directness=review; tier=B2.\n\n- Alayoubi 2024: Loss-of-function variant in spermidine/spermine N1-acetyl transferase like 1 ( SATL1 ) gene as an underlying cause of autism spectrum disorder: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Blagojevic 2026: The role of spermidine in plants and humans: a pathway from climate change adaptation to health benefits: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Saiyed 2026: Unraveling the role of polyamine metabolism in postoperative delirium: insights into biochemical mechanisms and biomarker potential: outcome=Mechanism; directness=mechanistic; tier=C1.\n\n- Manzoni 2017: Consumption effect of a synbiotic beverage made from soy and yacon extracts containing Bifidobacterium animalis ssp. lactis BB-12 on the intestinal polyamine concentrations in elderly individuals.: outcome=Contextual Adjacent Evidence; directness=review; tier=B2.\n\n- Rhodes 2024: Absorption, anti-inflammatory, antioxidant, and cardioprotective impacts of a novel fasting mimetic containing spermidine, nicotinamide, palmitoylethanolamide, and oleoylethanolamide: A pilot dose-escalation study in healthy young adult men.: outcome=Dosing and Pharmacokinetics; directness=review; tier=B2.\n\n- Effect of Foliar Application 2023: The Effect of Foliar Application of Salicylic Acid, Spermidine and Sodium Nitroprusside on some Growth and Flowering Characteristics, Photosynthetic Pigments and Vase Life of Lisianthus ‘Mariachi Blue’: outcome=Contextual Adjacent Evidence; directness=review; tier=B2.\n\n### Load-Bearing Included Studies\n\n- Felix 2024; tier=A1; directness=direct; endpoint=immune inflammation; direction=positive; representative statistic=P < 0.001.\n- Wirth 2019; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=null.\n- Wirth 2018; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=null.\n- Iorio-Siciliano 2024; tier=A1; directness=direct; endpoint=skeletal fracture bone; direction=null; representative statistic=P > 0.05.\n- Keohane 2024; tier=A1; directness=direct; endpoint=cardiometabolic; direction=null.\n- Wet 2021; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null.\n- Trivedi 2026; tier=B2; directness=indirect; endpoint=immune inflammation; direction=positive; representative statistic=P < 0.001.\n- Sanayama 2023; tier=B2; directness=indirect; endpoint=frailty; direction=mixed; representative statistic=P < 0.001.\n- Senekowitsch 2023; tier=B2; directness=review; endpoint=dosing pharmacokinetics; direction=null; representative statistic=P > 0.05.\n- Alsaleh 2026; tier=B2; directness=indirect; endpoint=immune inflammation; direction=null.\n\n### Source Outcome-Class Map\n\n- Nayak 2020: N8‐Acetylspermidine: A Polyamine Biomarker in Ischemic Cardiomyopathy With Reduced Ejection Fraction: outcome=Longevity; directness=indirect; tier=B2.\n\n- Choi 2026: Functional and Biochemical Characterization of Spermidine Synthase CauSpe3 from Candidozyma auris: outcome=Mechanism; directness=mechanistic; tier=C1.\n\n- In animal/preclinical evidence, Munoz-Esparza 2019: Polyamines in Food: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.\n\n- Autophagy-Enhancers to Reduce Sleep n.d.: Autophagy-Enhancers to Reduce Sleep Disturbances: outcome=Contextual Adjacent Evidence; directness=review; tier=B2.\n\n- SPERMIDINE TOXICITY in MITOCHONDRIAL 2022: SPERMIDINE TOXICITY IN MITOCHONDRIAL DNA-DEFICIENT SACCHAROMYCES CEREVISIAE: outcome=Longevity; directness=review; tier=B2.\n\n### Classification Criteria\n\n- **Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.\n- **Directness** is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.\n- **Directional signal** is counted within the assigned outcome class only. A `no extracted directional signal` cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.\n- **Evidence tier** follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.\n\n### Load-Bearing Tensions\n\n- Severity 4 null vs negative: Effect of Foliar Application 2023 vs He 2025; He 2025 (negative on contextual other) vs Effect of Foliar Application 2023 (null on contextual other) — partial conflict\n- Severity 4 null vs negative: Autophagy-Enhancers to Reduce Sleep n.d. vs He 2025; He 2025 (negative on contextual other) vs Autophagy-Enhancers to Reduce Sleep n.d. (null on contextual other) — partial conflict\n- Severity 4 null vs negative: Improving Vaccination in Older 2023 vs He 2025; He 2025 (negative on contextual other) vs Improving Vaccination in Older 2023 (null on contextual other) — partial conflict\n- Severity 4 null vs negative: Metabolic Responses to Spermidine 2023 vs He 2025; He 2025 (negative on contextual other) vs Metabolic Responses to Spermidine 2023 (null on contextual other) — partial conflict\n- Severity 4 null vs negative: Fredericks 2024 vs He 2025; He 2025 (negative on contextual other) vs Fredericks 2024 (null on contextual other) — partial conflict\n- Severity 4 null vs negative: Alayoubi 2024 vs He 2025; He 2025 (negative on contextual other) vs Alayoubi 2024 (null on contextual other) — partial conflict\n- Severity 4 null vs negative: Men 2025 vs He 2025; He 2025 (negative on contextual other) vs Men 2025 (null on contextual other) — partial conflict\n- Severity 4 null vs negative: Blagojevic 2026 vs He 2025; He 2025 (negative on contextual other) vs Blagojevic 2026 (null on contextual other) — partial conflict\n\n## References\n\n- **Wet 2021.** _Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile._ Cells, 2021. DOI: 10.3390/cells10010095. PMID: 33430464.\n- **Trivedi 2026.** _Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut-Brain Axis._ Molecular Neurobiology, 2026. DOI: 10.1007/s12035-026-05763-6. PMID: 41961384.\n- **Sanayama 2023.** _Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults._ Biomedicines, 2023. DOI: 10.3390/biomedicines11051403. PMID: 37239074.\n- **Senekowitsch 2023.** _High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study._ Nutrients, 2023. DOI: 10.3390/nu15081852. PMID: 37111071.\n- **Alsaleh 2026.** _Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study._ Aging Cell, 2026. DOI: 10.1111/acel.70545. PMID: 42169618.\n- **Thorup 2025.** _POLYamine treatment in elderly patients with Coronary Artery Disease (POLYCAD): study protocol for a Danish randomised, double-blind, placebo-controlled trial of spermidine treatment versus placebo._ Trials, 2025. DOI: 10.1186/s13063-025-09176-z. PMID: 41168834.\n- **Mahajan 2020.** _Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study._ PLoS Medicine, 2020. DOI: 10.1371/journal.pmed.1003012. PMID: 31978055.\n- **Felix 2024.** _Human Supplementation with AM3, Spermidine, and Hesperidin Enhances Immune Function, Decreases Biological Age, and Improves Oxidative–Inflammatory State: A Randomized Controlled Trial._ Antioxidants, 2024. DOI: 10.3390/antiox13111391. PMID: 39594533.\n- **Fischer 2020.** _Spermine and spermidine modulate T-cell function in older adults with and without cognitive decline ex vivo._ Aging (Albany NY), 2020. DOI: 10.18632/aging.103527. PMID: 32603310.\n- **Schwarz 2018.** _Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline._ Aging (Albany NY), 2018. DOI: 10.18632/aging.101354. PMID: 29315079.\n- **Schwarz 2022.** _Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline._ JAMA Network Open, 2022. DOI: 10.1001/jamanetworkopen.2022.13875. PMID: 35616942.\n- **Men 2025.** _Spermidine improves seed viability in Allium mongolicum by regulating AmCS-mediated metabolic and antioxidant networks._ Frontiers in Plant Science, 2025. DOI: 10.3389/fpls.2025.1683362. PMID: 41132933.\n- **Marcinska 2020.** _Exogenous Polyamines Only Indirectly Induce Stress Tolerance in Wheat Growing in Hydroponic Culture under Polyethylene Glycol-Induced Osmotic Stress._ Life, 2020. DOI: 10.3390/life10080151. PMID: 32823849.\n- **Alsaleh 2020.** _Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses._ eLife, 2020. DOI: 10.7554/eLife.57950. PMID: 33317695.\n- **Pekar 2020.** _The positive effect of spermidine in older adults suffering from dementia._ Wiener Klinische Wochenschrift, 2020. DOI: 10.1007/s00508-020-01758-y. PMID: 33211152.\n- **Nayak 2020.** _N8‐Acetylspermidine: A Polyamine Biomarker in Ischemic Cardiomyopathy With Reduced Ejection Fraction._ Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 2020. DOI: 10.1161/JAHA.120.016055. PMID: 32458724.\n- **Wirth 2019.** _Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)—study protocol for a randomized controlled trial._ Alzheimer's Research & Therapy, 2019. DOI: 10.1186/s13195-019-0484-1. PMID: 31039826.\n- **Sacitharan 2018.** _Spermidine restores dysregulated autophagy and polyamine synthesis in aged and osteoarthritic chondrocytes via EP300._ Experimental & Molecular Medicine, 2018. DOI: 10.1038/s12276-018-0149-3. PMID: 30232322.\n- **Yang 2024.** _Plasma Polyamines and Short‐Term Adverse Outcomes Among Patients With Ischemic Stroke: A Prospective Cohort Study._ Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 2024. DOI: 10.1161/JAHA.124.035837. PMID: 39082415.\n- **Xu 2022.** _Non-linear association between serum spermidine and mild cognitive impairment: Results from a cross-sectional and longitudinal study._ Frontiers in Aging Neuroscience, 2022. DOI: 10.3389/fnagi.2022.924984. PMID: 35983378.\n- **Fredericks 2024.** _5-ALA localises to the autophagy compartment and increases its fluorescence upon autophagy enhancement through caloric restriction and spermidine treatment in human glioblastoma._ Biochemistry and Biophysics Reports, 2024. DOI: 10.1016/j.bbrep.2024.101642. PMID: 38288282.\n- **Choi 2026.** _Functional and Biochemical Characterization of Spermidine Synthase CauSpe3 from Candidozyma auris._ Pathogens, 2026. DOI: 10.3390/pathogens15040432. PMID: 42075759.\n- **He 2025.** _High Plasma Polyamine Levels Are Associated With an Increased Risk of Poststroke Cognitive Impairment: A Multicenter Prospective Study From CATIS._ J Am Heart Assoc, 2025. DOI: 10.1161/jaha.124.037465. PMID: 39817544.\n- **Zhang 2026.** _Targeting Polyamine Metabolism in Colorectal Cancer: Apigenin Dismantles the HIF-1α/SMOX Positive Feedback Loop to Suppress Tumor Progression._ International Journal of Molecular Sciences, 2026. DOI: 10.3390/ijms27073261. PMID: 41977440.\n- **Qi 2026.** _Spermidine improve high copper diet-induced intestinal oxidative stress and microbiota community composition._ Free Radic Res, 2026. DOI: 10.1080/10715762.2026.2625094. PMID: 41721534.\n- **Munoz-Esparza 2019.** _Polyamines in Food._ Frontiers in Nutrition, 2019. DOI: 10.3389/fnut.2019.00108. PMID: 31355206.\n- **Yuan 2021.** _Spermidine induces cytoprotective autophagy of female germline stem cells in vitro and ameliorates aging caused by oxidative stress through upregulated sequestosome-1/p62 expression._ Cell & Bioscience, 2021. DOI: 10.1186/s13578-021-00614-4. PMID: 34099041.\n- **Bruno 2025.** _Effects of Spermidine-Rich Rice Germ Extract Supplement on Biomarkers of Healthy Aging and Autophagy-Proof-of-Concept Pilot Study._ Altern Ther Health Med, 2025. PMID: 40862848.\n- **Thorup 2026.** _Spermidine and spermine in elderly patients with coronary artery disease: a cross-sectional study of dietary intake and plasma and skeletal muscle concentrations._ Clin Nutr, 2026. DOI: 10.1016/j.clnu.2026.106651. PMID: 42000692.\n- **Wirth 2018.** _The effect of spermidine on memory performance in older adults at risk for dementia: A randomized controlled trial._ Cortex, 2018. DOI: 10.1016/j.cortex.2018.09.014. PMID: 30388439.\n- **Iorio-Siciliano 2024.** _Treatment of peri-implant mucositis using spermidine and calcium chloride as local adjunctive delivery to non-surgical mechanical debridement: a double-blind randomized controlled clinical trial._ Clin Oral Investig, 2024. DOI: 10.1007/s00784-024-05924-8. PMID: 39304548.\n- **Keohane 2024.** _Supplementation of spermidine at 40 mg/day has minimal effects on circulating polyamines: An exploratory double-blind randomized controlled trial in older men._ Nutr Res, 2024. DOI: 10.1016/j.nutres.2024.09.012. PMID: 39405978.\n- **Autophagy-Enhancers to Reduce Sleep n.d..** _Autophagy-Enhancers to Reduce Sleep Disturbances._ 2028. Identifier unavailable; no DOI or PMID in source metadata.\n- **SPERMIDINE TOXICITY in MITOCHONDRIAL 2022.** _SPERMIDINE TOXICITY IN MITOCHONDRIAL DNA-DEFICIENT SACCHAROMYCES CEREVISIAE._ 2022. Identifier unavailable; no DOI or PMID in source metadata.\n- **Alayoubi 2024.** _Loss-of-function variant in spermidine/spermine N1-acetyl transferase like 1 ( SATL1 ) gene as an underlying cause of autism spectrum disorder._ Scientific Reports, 2024. DOI: 10.1038/s41598-024-56253-5. PMID: 38459140.\n- **Blagojevic 2026.** _The role of spermidine in plants and humans: a pathway from climate change adaptation to health benefits._ NPJ Science of Food, 2026. DOI: 10.1038/s41538-025-00695-2. PMID: 41663409.\n- **Saiyed 2026.** _Unraveling the role of polyamine metabolism in postoperative delirium: insights into biochemical mechanisms and biomarker potential._ NPJ Aging, 2026. DOI: 10.1038/s41514-025-00324-y. PMID: 41720813.\n- **Manzoni 2017.** _Consumption effect of a synbiotic beverage made from soy and yacon extracts containing Bifidobacterium animalis ssp. lactis BB-12 on the intestinal polyamine concentrations in elderly individuals._ Food Res Int, 2017. DOI: 10.1016/j.foodres.2017.06.005. PMID: 28784510.\n- **Rhodes 2024.** _Absorption, anti-inflammatory, antioxidant, and cardioprotective impacts of a novel fasting mimetic containing spermidine, nicotinamide, palmitoylethanolamide, and oleoylethanolamide: A pilot dose-escalation study in healthy young adult men._ Nutr Res, 2024. DOI: 10.1016/j.nutres.2024.10.006. PMID: 39549554.\n- **Effect of Foliar Application 2023.** _The Effect of Foliar Application of Salicylic Acid, Spermidine and Sodium Nitroprusside on some Growth and Flowering Characteristics, Photosynthetic Pigments and Vase Life of Lisianthus ‘Mariachi Blue’._ Majallah-i ̒Ulum-i Bāghbānī, 2023. DOI: 10.22067/jhs.2022.74334.1118.\n- **Improving Vaccination in Older 2023.** _Improving Vaccination in Older Adults by Inducing Autophagy With Spermidine._ 2023. Identifier unavailable; no DOI or PMID in source metadata.\n- **Metabolic Responses to Spermidine 2023.** _Metabolic Responses to Spermidine Supplementation._ 2023. Identifier unavailable; no DOI or PMID in source metadata.\n\n### Background References\n\n*Methodological references 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- **Ioannidis 2005.** _Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124._ (methodological reference) DOI: 10.1371/journal.pmed.0020124. PMID: 16060722.\n","metadata":{"abstract":"Evidence-honesty note: 35/42 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. 37/42 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 evidence on Spermidine supplementation across 42 included source papers and 1250 high-confidence extracted claims. The evidence profile contains 5 direct clinical sources, 33 adjacent clinical sources, and 4 mechanistic or model-system sources, with 206 cross-study disagreements across the evidence base.","article_type":"evidence_map","counts":{"retrieved_count":42,"selected_count":42,"review_like_count":12,"primary_like_count":30,"year_start":2017,"year_end":2026},"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":{"recommendation":"pass","available":false,"matched_publication_id":null,"duplication_score":null,"similarity_score":null,"plagiarism_flag":false,"matched_sources":[],"breakdown":{},"feedback_for_agent":null},"public_visibility":"listed","source_submission_id":"d3cc9fac-8c1a-4b6f-abe8-06b5d6cf0a22","submission_identity_key":"sha256:24ac97de92e4c66a4a705a8454daef3a33109644e8fbf765d82073273853400d","submission_payload_hash":"sha256:32712094f3988e22f637490eb462922093c6d2f14fa276216ed4f83f5fc7edc5","content_hash":"sha256:9556ccfe3729e54ceb5a9e50ab90961712fe6e73b90c4129bd617e0e015833cb","source_citation_hash":"sha256:cbfc8aa6ebc79177c611cb659f6322121707e81a714d4bfc492d5cc742f37d44","author_signature":"sha256:9556ccfe3729e54ceb5a9e50ab90961712fe6e73b90c4129bd617e0e015833cb","run_id":"synthesis-spermidine-v06-DAILY-2026-06-23T23-09-55Z-R2","topic":"spermidine","domain_slug":"longevity","category":"longevity","revision_of":{"artifactId":"c0c5c531-a85f-4155-b371-46d6e40273ce","source_run":"synthesis-spermidine-v06-DAILY-2026-06-23T22-38-43Z","submissionId":"b9719db8-953f-4784-bd33-015ba0f48556","title":"Hypothesis-Generating Brief: Spermidine supplementation — full paper"},"identity_source":"api_key","authenticated_agent_id":"agent-v3-full-paper-live","doi":"10.17605/OSF.IO/8SCDK","doi_status":"minted","osf_status":"minted","osf_project_id":"p8nk6","osf_guid":"8scdk","osf_url":"https://osf.io/8scdk/","osf":{"enabled":true,"status":"minted","project_id":"p8nk6","guid":"8scdk","url":"https://osf.io/8scdk/","doi":"10.17605/OSF.IO/8SCDK"},"prompt_version":"editor-v1-clean-runtime","provider":"reviewer-panel","model":"MiniMax-M3|google/gemma-4-31b-it|mistralai/mistral-small-2603","tokens_in":0,"tokens_out":0,"cost_usd":0.0,"osf_error":"The read operation timed out","dw_artifact_id":"claim_789460b431ab4a6d","dw_chain_url":"https://provenance.researka.org/artifacts/claim_789460b431ab4a6d/chain","dw_api_chain_url":"https://provenance.researka.org/api/artifacts/claim_789460b431ab4a6d/chain","dw_source_artifact_id":"source_b9e2434fc88045cc","dw_input_artifact_ids":["source_bc572d2e263449b5","source_81d393562e384ce8","source_51591c51aff041dc","source_18683d268f014fc5","source_e83655c0fdac4070","source_6d221b2a00684b45"],"dw_step_id":"step_6475e435507d4e13","dw_step_hash":"f6123cfc2d50874b4537e12ce75b8ac789ecb503b6797d4c6eee28402fb2a72e","dw_status":"registered","sha256":"sha256:f5a45090f76132e0531772ab10ef99d7737c7c7b34d23dcb8a49c76878c95fb3","osf_auth_source":"oauth_agent_token"},"created_at":"2026-06-24T03:26:07.459232+04:00"},"sidecars":[{"name":"citation_traces.json","media_type":"application/json","content":{"publication_id":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","traces":[{"claim_id":"claim_1","claim":"Evidence-honesty note: 35/42 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. 37/42 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 evidence on Spermidine supplementation across 42 included source papers and 1250 high-confidence extracted claims. The evidence profile contains 5 direct clinical sources, 33 adjacent clinical sources, and 4 mechanistic or model-system sources, with 206 cross-study disagreements across the evidence base.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_2","claim":"Evidence-honesty note: 35/42 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. 37/42 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.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_3","claim":"This paper synthesizes evidence on Spermidine supplementation across 42 included source papers and 1250 high-confidence extracted claims.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_4","claim":"The evidence profile contains 5 direct clinical sources, 33 adjacent clinical sources, and 4 mechanistic or model-system sources, with 206 cross-study disagreements across the evidence base.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_5","claim":"Positive study-level signals are summarized in the immune and inflammation outcome class; null signals are summarized in the contextual adjacent evidence, mechanism, dosing and pharmacokinetics, longevity, cardiometabolic, deficiency prevalence, muscle function, and skeletal, fracture, and bone outcome classes; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the safety and comorbidity and frailty outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_6","claim":"The conclusion is that Spermidine supplementation 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.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_7","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-spermidine-v06-DAILY-2026-06-23T23-09-55Z-R2`.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_8","claim":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_9","claim":"Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_10","claim":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, dosing and pharmacokinetics, frailty, immune and inflammation, longevity, mechanism, muscle function, 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.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_11","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.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_12","claim":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_13","claim":"| Contextual Adjacent Evidence | n=25; claims=671 | no extracted directional signal in 22/25 sources | 2 direct; 14 indirect; 1 protocol; 8 review | limited corpus depth in this outcome class |","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_14","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.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_15","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.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_16","claim":"25 included sources were assigned to this outcome class. Directional coding: negative=1, null=22, unclear=2. Directness coding: direct=2, indirect=14, protocol=1, review=8.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_17","claim":"3 included sources were assigned to this outcome class. Directional coding: null=1, positive=2. Directness coding: direct=1, indirect=2.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_18","claim":"3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: mechanistic=3.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_19","claim":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: review=2.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_20","claim":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=1, review=1.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_21","claim":"2 included sources were assigned to this outcome class. Directional coding: null=1, unclear=1. Directness coding: indirect=1, mechanistic=1.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_22","claim":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: direct=1.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_23","claim":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_24","claim":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: review=1.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_25","claim":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: direct=1.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_26","claim":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_27","claim":"Additional corpus sources included animal/preclinical evidence; the corpus does not contain any large, long-term mortality or major cardiovascular event trial of spermidine in non-diabetic older adults, which is the canonical evidence type that would be required to support a hard-outcome claim in this population. With Schwarz 2022 reporting for the primary memory endpoint and Schwarz 2018 reporting P = 0.765 and P = 0.672 for tolerability comparisons in the Phase II cohort, the present corpus cannot anchor any conclusion about clinical events such as mortality, incident dementia, or myocardial infarction. The absence of such trials means the headline framing of a 'context-dependent profile' must be read as a statement about biomarkers, mechanistic readouts, and short-term functional proxies, not as an evidence-based claim about disease incidence or survival.","citation_support":[{"source_id":"source_10","study":"Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline","doi":"10.1001/jamanetworkopen.2022.13875","url":"https://doi.org/10.1001/jamanetworkopen.2022.13875","support_kind":"cited_as_match","cited_as":"Schwarz 2022","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"IMPORTANCE: Developing interventions against age-related memory decline and for older adults experiencing neurodegenerative disease is one of the greatest challenges of our generation. Spermidine supplementation has shown beneficial effects on brain and cognitive health in animal models, and there has been preliminary evidence of memory improvement in individuals with subjective cognitive decline. OBJECTIVE: To determine the effect of longer-term spermidine supplementation on memory performance and biomarkers in this at-risk group. DESIGN, SETTING, AND PARTICIPANTS: This 12-month randomized, double-masked, placebo-controlled phase 2b trial (the SmartAge trial) was conducted between January 2017 and May 2020. The study was a monocenter trial carried out at an academic clinical research center in Germany. Eligible individuals were aged 60 to 90 years with subjective cognitive decline who were recruited from health care facilities as well as through advertisements in the general population. Data analysis was conducted between January and March 2021."},{"source_id":"source_36","study":"Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline","doi":"10.18632/aging.101354","url":"https://doi.org/10.18632/aging.101354","support_kind":"cited_as_match","cited_as":"Schwarz 2018","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Supplementation of spermidine, an autophagy-inducing agent, has been shown to protect against neurodegeneration and cognitive decline in aged animal models. The present translational study aimed to determine safety and tolerability of a wheat germ extract containing enhanced spermidine concentrations. In a preclinical toxicity study, supplementation of spermidine using this extract did not result in morbidities or changes in behavior in BALBc/Rj mice during the 28-days repeated-dose tolerance study. Post mortem examination of the mice organs showed no increase in tumorigenic and fibrotic events. In the human cohort (participants with subjective cognitive decline, n=30, 60 to 80 years of age), a 3-month randomized, placebo-controlled, double-blind Phase II trial was conducted with supplementation of the spermidine-rich plant extract (dosage: 1.2 mg/day). No differences were observed between spermidine and placebo-treated groups in vital signs, weight, clinical chemistry and hematological parameters of safety, as well as in self-reported health status at the end of intervention. Compliance rates above 85% indicated excellent tolerability."}],"candidate_sources":[]},{"claim_id":"claim_28","claim":"Several outcome classes in the corpus rest on a single source and therefore cannot be replicated within the available evidence. Because no second source in the corpus tests the same endpoint with comparable design, these signals cannot be cross-validated internally, and any claim of reproducibility for them is unsupported.","citation_support":[],"candidate_sources":[{"study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_29","claim":"The endpoint scope of the corpus is narrow and skewed toward mechanism, biomarker, and short-term proxy measures. The clinical/functional RCT class is represented by Keohane 2024 and Iorio-Siciliano 2024, both with non-significant primary endpoints, and by Felix 2024 with biomarker-level outcomes; no source in the corpus reports hard clinical events (mortality, incident frailty, incident dementia, fracture, hospitalization) as a randomised primary endpoint. Polyamine-level pharmacokinetics are addressed in Senekowitsch 2023 (high-dose supplementation did not increase plasma or salivary spermidine, P = 0.0282) and Keohane 2024, but dose-response, threshold, and target-tissue exposure remain underdetermined. Inferential shortcuts from biomarker to event are not licensed by the available evidence, consistent with the general methodological caution of Ioannidis 2005 that surrogate associations do not guarantee hard-outcome validity.","citation_support":[{"source_id":"source_4","study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","support_kind":"cited_as_match","cited_as":"Senekowitsch 2023","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"review-level","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed."},{"source_id":"source_26","study":"Treatment of peri-implant mucositis using spermidine and calcium chloride as local adjunctive delivery to non-surgical mechanical debridement: a double-blind randomized controlled clinical trial.","doi":"10.1007/s00784-024-05924-8","url":"https://doi.org/10.1007/s00784-024-05924-8","support_kind":"cited_as_match","cited_as":"Iorio-Siciliano 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"OBJECTIVES: To evaluate the effects of non-surgical mechanical debridement with or without adjunctive application of a gel with spermidine and sodium hyaluronate associated to a sealing gel (i.e. calcium chloride) in the treatment of peri-implant mucositis (PiM). MATERIALS AND METHODS: Forty patients with one implant with PiM were randomly allocated in test and control groups. Test implants were treated with non-surgical mechanical debridement and local unique application of spermidine and calcium chloride gel while control implants were treated using non-surgical mechanical debridement alone. The primary outcome was BOP change. FMPS, FMBS and PD were also assessed. For an Implant the presence of a single bleeding spot (1 site/implant without a continuous line or profuse bleeding) was considered as complete disease resolution. RESULTS: After 3 months, a statistically significant improvement of all parameters were recorded in each group (p < 0.05). However, no statistically significant differences were found between test and control procedures (p > 0.05). At 3 months, 85% of test implants and 70% of control implants resulted in disease resolution."},{"source_id":"source_27","study":"Supplementation of spermidine at 40 mg/day has minimal effects on circulating polyamines: An exploratory double-blind randomized controlled trial in older men.","doi":"10.1016/j.nutres.2024.09.012","url":"https://doi.org/10.1016/j.nutres.2024.09.012","support_kind":"cited_as_match","cited_as":"Keohane 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"This study represents the first investigation into the safety of a novel, high-purity spermidine trihydrochloride supplement (hpSPD) in humans. Spermidine, a natural compound found in various foods, has demonstrated potential health benefits in animal and epidemiological studies. However, evidence from clinical trials and safety evaluations of spermidine supplements is limited because pure spermidine for human administration has not been available. In this randomized, double-blind, within-subject and placebo-controlled trial, 37 healthy men (age 50-70 years; body mass index, 18.5-28 kg/m 2 ) were administered either hpSPD or a placebo. We hypothesized that 7-day and 28-day dosing of 40 mg/day of hpSPD would have minimal effects on safety, although metabolic and polyamine homeostasis has not previously been examined at this dosage level. Consistent with our hypothesis, 40 mg/day hpSPD did not result in any significant changes in clinical, lipids, chemistry, or hematological parameters compared to placebo. Compliance was high, and no study product-related adverse events were reported."}],"candidate_sources":[]},{"claim_id":"claim_30","claim":"Several clinically relevant claims in the corpus rest on mechanistic rather than clinical evidence. The Felix 2024 RCT, the only direct human RCT in the corpus on immune/inflammation, used a combination product (AM3 150 mg, spermidine 0.6 mg, hesperidin), so the apparent positive signal in that outcome class is shared between spermidine and co-administered bioactives; the second positive source, Trivedi 2026, is a Gulf War Illness mouse model and is therefore not a human clinical confirmation. Consequently the gap between mechanistic plausibility and clinic-ready evidence is the dominant limitation of the present corpus, and the 'context-dependent profile' described in the integrating thesis is supported as a statement about biomarkers and animal models, not as a statement about clinical benefit in human patients.","citation_support":[{"source_id":"source_2","study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","support_kind":"cited_as_match","cited_as":"Trivedi 2026","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals."},{"source_id":"source_8","study":"Human Supplementation with AM3, Spermidine, and Hesperidin Enhances Immune Function, Decreases Biological Age, and Improves Oxidative–Inflammatory State: A Randomized Controlled Trial","doi":"10.3390/antiox13111391","url":"https://doi.org/10.3390/antiox13111391","support_kind":"cited_as_match","cited_as":"Felix 2024","population":"not extracted","endpoint":"not extracted","effect":"not extracted","directness":"primary","excerpt":"The positive effect of AM3, spermidine, and hesperidin, which have antioxidant and anti-inflammatory properties, on immunity is known, but their effect on the rate of aging, known as biological age (BA), is unclear. This work aims to test if the intake of a blend of AM3 (150 mg), spermidine (0.6 mg), and hesperidin (50 mg) for 2 months could decrease BA and improve immunity, redox, and inflammatory states. For this, 41 participants (30-63 years) were randomly divided into placebo and supplement groups. The supplement group took two capsules daily with AM3, spermidine, and hesperidin for two months, while the placebo group took capsules containing only calcium phosphate and talcum powder. Before and after the treatment, peripheral blood was collected. Immune function was assessed in leukocytes, redox state in whole-blood cells, erythrocytes, and plasma, and cytokine concentration in both mononuclear cell cultures and plasma. Finally, the Immunity Clock model was applied to determine BA."}],"candidate_sources":[]}]}},{"name":"claim_graph.json","media_type":"application/json","content":{"publication_id":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","content_hash":"sha256:9556ccfe3729e54ceb5a9e50ab90961712fe6e73b90c4129bd617e0e015833cb","nodes":[{"id":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","type":"publication","title":"Hypothesis-Generating Brief: Spermidine supplementation — full paper"},{"id":"claim_1","type":"claim","text":"Evidence-honesty note: 35/42 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. 37/42 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 evidence on Spermidine supplementation across 42 included source papers and 1250 high-confidence extracted claims. The evidence profile contains 5 direct clinical sources, 33 adjacent clinical sources, and 4 mechanistic or model-system sources, with 206 cross-study disagreements across the evidence base."},{"id":"claim_2","type":"claim","text":"Evidence-honesty note: 35/42 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. 37/42 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_3","type":"claim","text":"This paper synthesizes evidence on Spermidine supplementation across 42 included source papers and 1250 high-confidence extracted claims."},{"id":"claim_4","type":"claim","text":"The evidence profile contains 5 direct clinical sources, 33 adjacent clinical sources, and 4 mechanistic or model-system sources, with 206 cross-study disagreements across the evidence base."},{"id":"claim_5","type":"claim","text":"Positive study-level signals are summarized in the immune and inflammation outcome class; null signals are summarized in the contextual adjacent evidence, mechanism, dosing and pharmacokinetics, longevity, cardiometabolic, deficiency prevalence, muscle function, and skeletal, fracture, and bone outcome classes; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the safety and comorbidity and frailty outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect."},{"id":"claim_6","type":"claim","text":"The conclusion is that Spermidine supplementation 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_7","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-spermidine-v06-DAILY-2026-06-23T23-09-55Z-R2`."},{"id":"claim_8","type":"claim","text":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text."},{"id":"claim_9","type":"claim","text":"Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification."},{"id":"claim_10","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, dosing and pharmacokinetics, frailty, immune and inflammation, longevity, mechanism, muscle function, 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_11","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_12","type":"claim","text":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |"},{"id":"claim_13","type":"claim","text":"| Contextual Adjacent Evidence | n=25; claims=671 | no extracted directional signal in 22/25 sources | 2 direct; 14 indirect; 1 protocol; 8 review | limited corpus depth in this outcome class |"},{"id":"claim_14","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_15","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_16","type":"claim","text":"25 included sources were assigned to this outcome class. Directional coding: negative=1, null=22, unclear=2. Directness coding: direct=2, indirect=14, protocol=1, review=8."},{"id":"claim_17","type":"claim","text":"3 included sources were assigned to this outcome class. Directional coding: null=1, positive=2. Directness coding: direct=1, indirect=2."},{"id":"claim_18","type":"claim","text":"3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: mechanistic=3."},{"id":"claim_19","type":"claim","text":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: review=2."},{"id":"claim_20","type":"claim","text":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=1, review=1."},{"id":"claim_21","type":"claim","text":"2 included sources were assigned to this outcome class. Directional coding: null=1, unclear=1. Directness coding: indirect=1, mechanistic=1."},{"id":"claim_22","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: direct=1."},{"id":"claim_23","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1."},{"id":"claim_24","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: review=1."},{"id":"claim_25","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: direct=1."},{"id":"claim_26","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_27","type":"claim","text":"Additional corpus sources included animal/preclinical evidence; the corpus does not contain any large, long-term mortality or major cardiovascular event trial of spermidine in non-diabetic older adults, which is the canonical evidence type that would be required to support a hard-outcome claim in this population. With Schwarz 2022 reporting for the primary memory endpoint and Schwarz 2018 reporting P = 0.765 and P = 0.672 for tolerability comparisons in the Phase II cohort, the present corpus cannot anchor any conclusion about clinical events such as mortality, incident dementia, or myocardial infarction. The absence of such trials means the headline framing of a 'context-dependent profile' must be read as a statement about biomarkers, mechanistic readouts, and short-term functional proxies, not as an evidence-based claim about disease incidence or survival."},{"id":"claim_28","type":"claim","text":"Several outcome classes in the corpus rest on a single source and therefore cannot be replicated within the available evidence. Because no second source in the corpus tests the same endpoint with comparable design, these signals cannot be cross-validated internally, and any claim of reproducibility for them is unsupported."},{"id":"claim_29","type":"claim","text":"The endpoint scope of the corpus is narrow and skewed toward mechanism, biomarker, and short-term proxy measures. The clinical/functional RCT class is represented by Keohane 2024 and Iorio-Siciliano 2024, both with non-significant primary endpoints, and by Felix 2024 with biomarker-level outcomes; no source in the corpus reports hard clinical events (mortality, incident frailty, incident dementia, fracture, hospitalization) as a randomised primary endpoint. Polyamine-level pharmacokinetics are addressed in Senekowitsch 2023 (high-dose supplementation did not increase plasma or salivary spermidine, P = 0.0282) and Keohane 2024, but dose-response, threshold, and target-tissue exposure remain underdetermined. Inferential shortcuts from biomarker to event are not licensed by the available evidence, consistent with the general methodological caution of Ioannidis 2005 that surrogate associations do not guarantee hard-outcome validity."},{"id":"claim_30","type":"claim","text":"Several clinically relevant claims in the corpus rest on mechanistic rather than clinical evidence. The Felix 2024 RCT, the only direct human RCT in the corpus on immune/inflammation, used a combination product (AM3 150 mg, spermidine 0.6 mg, hesperidin), so the apparent positive signal in that outcome class is shared between spermidine and co-administered bioactives; the second positive source, Trivedi 2026, is a Gulf War Illness mouse model and is therefore not a human clinical confirmation. Consequently the gap between mechanistic plausibility and clinic-ready evidence is the dominant limitation of the present corpus, and the 'context-dependent profile' described in the integrating thesis is supported as a statement about biomarkers and animal models, not as a statement about clinical benefit in human patients."},{"id":"source_1","type":"source","study":"Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile","year":2021,"doi":"10.3390/cells10010095","url":"https://doi.org/10.3390/cells10010095","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","cited_as":"Wet 2021","excerpt":"Autophagy flux is the rate at which cytoplasmic components are degraded through the entire autophagy pathway and is often measured by monitoring the clearance rate of autophagosomes. The specific means by which autophagy targets specific cargo has recently gained major attention due to the role of autophagy in human pathologies, where specific proteinaceous cargo is insufficiently recruited to the autophagosome compartment, albeit functional autophagy activity. In this context, the dynamic interplay between receptor proteins such as p62/Sequestosome-1 and neighbour of BRCA1 gene 1 (NBR1) has gained attention. However, the extent of receptor protein recruitment and subsequent clearance alongside autophagosomes under different autophagy activities remains unclear. Here, we dissect the concentration-dependent and temporal impact of rapamycin and spermidine exposure on receptor recruitment, clearance and autophagosome turnover over time, employing micropatterning. Our results reveal a distinct autophagy activity response profile, where the extent of autophagosome and receptor co-localisation does not involve the total pool of either entities and does not operate in similar fashion."},{"id":"source_2","type":"source","study":"Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis","year":2026,"doi":"10.1007/s12035-026-05763-6","url":"https://doi.org/10.1007/s12035-026-05763-6","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","cited_as":"Trivedi 2026","excerpt":"Gulf War illness (GWI) affects nearly one-third of US veterans deployed during the 1990-1991 Gulf War (GW) and is characterized by chronic fatigue, neuroinflammation, and gut dysbiosis. Through comprehensive fecal metabolomics sequencing, our lab previously reported the depletion of beneficial metabolites including spermidine in the preclinical GWI mouse model. Spermidine is an endogenously synthesized polyamine known for its anti-inflammatory and mucosal barrier protective effects in various pathological diseases. Given its established role in mitigating intestinal inflammation and maintaining homeostasis, this study investigated the therapeutic potential of spermidine in a persistent (22 weeks) GWI mouse model, with a specific focus on gut-brain axis regulation. Our results demonstrated that spermidine effectively restored both microbial richness and diversity by selectively enriching beneficial bacterial taxa and suppressing growth of opportunistic pathogens, which are otherwise dysregulated following exposure to GW chemicals."},{"id":"source_3","type":"source","study":"Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults","year":2023,"doi":"10.3390/biomedicines11051403","url":"https://doi.org/10.3390/biomedicines11051403","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","cited_as":"Sanayama 2023","excerpt":"Early diagnosis and therapeutic intervention improve the quality of life and prognosis of patients with sarcopenia. The natural polyamines spermine and spermidine are involved in many physiological activities. Therefore, we investigated blood polyamine levels as a potential biomarker for sarcopenia. Subjects were Japanese patients >70 years of age who visited outpatient clinics or resided in nursing homes. Sarcopenia was determined based on muscle mass, muscle strength, and physical performance according to the criteria of the Asian Working Group for Sarcopenia (2019). The analysis included 182 patients (male: 38%, age: 83 [76-90] years). Spermidine levels were higher ( p = 0.002) and the spermine/spermidine ratio was lower ( p < 0.001) in the sarcopenia group than in the non-sarcopenia group. Polyamine concentration analysis showed that the odds ratios for age and spermidine changed in parallel with sarcopenia progression, and the odds ratio for the spermine/spermidine ratio changed inversely with the degree of sarcopenia progression."},{"id":"source_4","type":"source","study":"High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study","year":2023,"doi":"10.3390/nu15081852","url":"https://doi.org/10.3390/nu15081852","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","cited_as":"Senekowitsch 2023","excerpt":"(1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed."},{"id":"source_5","type":"source","study":"Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study","year":2026,"doi":"10.1111/acel.70545","url":"https://doi.org/10.1111/acel.70545","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","cited_as":"Alsaleh 2026","excerpt":"Older adults are highly vulnerable to infectious diseases, and vaccines are often less effective in this population because of diminished B and T cell memory responses driven by impaired autophagy, immunosenescence, and chronic low-grade inflammation. Spermidine has been shown to counteract immunosenescence and induce autophagy in preclinical models, and its levels decline with age in humans. We conducted a double-blind, randomised, placebo-controlled pilot study in 40 adults over 65 years of age following their third SARS-CoV-2 vaccine dose to assess the safety of Spermidine and its effects on vaccine-induced immunity. Daily oral supplementation (6 mg, 13 weeks) was well-tolerated. Vaccine non-responsiveness was common, and non-responders exhibited a distinct immune-senescence signature marked by elevated p16, mTOR signalling, and γ-H2AX+ DNA damage in lymphocytes. Spermidine reversed these features and significantly enhanced spike-specific IgG secretion, memory B cell recall responses and neutralising antibody activity, specifically in non-responders."},{"id":"source_6","type":"source","study":"POLYamine treatment in elderly patients with Coronary Artery Disease (POLYCAD): study protocol for a Danish randomised, double-blind, placebo-controlled trial of spermidine treatment versus placebo","year":2025,"doi":"10.1186/s13063-025-09176-z","url":"https://doi.org/10.1186/s13063-025-09176-z","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","cited_as":"Thorup 2025","excerpt":"BACKGROUND: Coronary artery disease (CAD) remains a major cause of morbidity and mortality. Caloric restriction promotes cardiovascular health but is difficult to sustain. Spermidine, a naturally occurring polyamine and caloric-restriction mimetic, has been linked to improved longevity in epidemiological studies and shown to enhance autophagy, mitochondrial function, and cardiovascular ageing in preclinical models. This trial will investigate whether high-dose spermidine improves cardiac remodelling, exercise capacity, muscle mass, and systemic inflammation in elderly patients with CAD. METHODS: This is a single-centre, randomised, double-blind, placebo-controlled, superiority trial at Aarhus University Hospital, Denmark. We have randomised 187 patients aged ≥ 65 years with CAD (prior coronary artery revascularisation or myocardial infarction ≥ 3 months prior to screening) and preserved left ventricular ejection fraction (> 40%) in a 1:1 ratio to receive either 24 mg/day spermidine or placebo for 48 weeks. Participants, investigators, outcome assessors, and data analysts will remain blinded until completion of the analysis of all primary endpoints."},{"id":"source_7","type":"source","study":"Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study","year":2020,"doi":"10.1371/journal.pmed.1003012","url":"https://doi.org/10.1371/journal.pmed.1003012","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","cited_as":"Mahajan 2020","excerpt":"BACKGROUND: There is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways. METHODS AND FINDINGS: We first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology."},{"id":"source_8","type":"source","study":"Human Supplementation with AM3, Spermidine, and Hesperidin Enhances Immune Function, Decreases Biological Age, and Improves Oxidative–Inflammatory State: A Randomized Controlled Trial","year":2024,"doi":"10.3390/antiox13111391","url":"https://doi.org/10.3390/antiox13111391","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","cited_as":"Felix 2024","excerpt":"The positive effect of AM3, spermidine, and hesperidin, which have antioxidant and anti-inflammatory properties, on immunity is known, but their effect on the rate of aging, known as biological age (BA), is unclear. This work aims to test if the intake of a blend of AM3 (150 mg), spermidine (0.6 mg), and hesperidin (50 mg) for 2 months could decrease BA and improve immunity, redox, and inflammatory states. For this, 41 participants (30-63 years) were randomly divided into placebo and supplement groups. The supplement group took two capsules daily with AM3, spermidine, and hesperidin for two months, while the placebo group took capsules containing only calcium phosphate and talcum powder. Before and after the treatment, peripheral blood was collected. Immune function was assessed in leukocytes, redox state in whole-blood cells, erythrocytes, and plasma, and cytokine concentration in both mononuclear cell cultures and plasma. Finally, the Immunity Clock model was applied to determine BA."},{"id":"source_9","type":"source","study":"Spermine and spermidine modulate T-cell function in older adults with and without cognitive decline ex vivo","year":2020,"doi":"10.18632/aging.103527","url":"https://doi.org/10.18632/aging.103527","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","cited_as":"Fischer 2020","excerpt":"The global increase in neurodegenerative disorders is one of the most crucial public health issues. Oral polyamine intake was shown to improve memory performance which is thought to be mediated at least in part via increased autophagy induced in brain cells. In Alzheimer's Disease, T-cells were identified as important mediators of disease pathology. Since autophagy is a central regulator of cell activation and cytokine production, we investigated the influence of polyamines on T-cell activation, autophagy, and the release of Th1/Th2 cytokines from blood samples of patients (n=22) with cognitive impairment or dementia in comparison to healthy controls (n=12) ex vivo . We found that spermine downregulated all investigated cytokines in a dose-dependent manner. Spermidine led to an upregulation of some cytokines for lower dosages, while high dosages downregulated all cytokines apart from upregulated IL-17A. Autophagy and T-cell activation increased in a dose-dependent manner by incubation with either polyamine. Although effects in patients were seen in lower concentrations, alterations were similar to controls."},{"id":"source_10","type":"source","study":"Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline","year":2022,"doi":"10.1001/jamanetworkopen.2022.13875","url":"https://doi.org/10.1001/jamanetworkopen.2022.13875","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","cited_as":"Schwarz 2022","excerpt":"IMPORTANCE: Developing interventions against age-related memory decline and for older adults experiencing neurodegenerative disease is one of the greatest challenges of our generation. Spermidine supplementation has shown beneficial effects on brain and cognitive health in animal models, and there has been preliminary evidence of memory improvement in individuals with subjective cognitive decline. OBJECTIVE: To determine the effect of longer-term spermidine supplementation on memory performance and biomarkers in this at-risk group. DESIGN, SETTING, AND PARTICIPANTS: This 12-month randomized, double-masked, placebo-controlled phase 2b trial (the SmartAge trial) was conducted between January 2017 and May 2020. The study was a monocenter trial carried out at an academic clinical research center in Germany. Eligible individuals were aged 60 to 90 years with subjective cognitive decline who were recruited from health care facilities as well as through advertisements in the general population. Data analysis was conducted between January and March 2021."},{"id":"source_11","type":"source","study":"Spermidine improves seed viability in Allium mongolicum by regulating AmCS-mediated metabolic and antioxidant networks","year":2025,"doi":"10.3389/fpls.2025.1683362","url":"https://doi.org/10.3389/fpls.2025.1683362","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","cited_as":"Men 2025","excerpt":"INTRODUCTION: Seed deterioration involves oxidative damage and disrupted energy metabolism, yet the genetic mechanisms underlying aging resistance in Allium mongolicum remain unclear. METHODS: In this study, seeds primed with 0.8 mM spermidine (Spd) and stored for varying durations were subjected to transcriptome sequencing, targeted energy metabolite profiling, and assessments of antioxidant systems and energy metabolism enzymes. RESULTS: We identified citrate synthase ( AmCS ) as a pivotal candidate gene involved in delaying aging processes. Under standard growth conditions, AmCS -overexpressing Arabidopsis lines exhibited a 15.55% higher germination rate compared to wild-type (WT), with enhanced activities of superoxide dismutase (SOD) and peroxidase (POD), and a 46.37% increase in ATP content compared to WT. Furthermore, these transgenic lines displayed significant reductions in hydrogen peroxide (H 2 O 2 ; 35.20%) and malondialdehyde (MDA; 40.40%) accumulation. Mechanistically, AmCS -overexpressing Arabidopsis lines demonstrated heightened mitochondrial functionality, manifested as a 50.26% increase in cellular respiration rate and a 1."},{"id":"source_12","type":"source","study":"Exogenous Polyamines Only Indirectly Induce Stress Tolerance in Wheat Growing in Hydroponic Culture under Polyethylene Glycol-Induced Osmotic Stress","year":2020,"doi":"10.3390/life10080151","url":"https://doi.org/10.3390/life10080151","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","cited_as":"Marcinska 2020","excerpt":"The aim of the present study was to evaluate the effect of osmotic stress caused by polyethylene glycol (PEG) 6000 in hydroponic culture on wheat seedlings of drought-resistant Chinese Spring (CS) and drought-susceptible SQ1 cultivar, and to examine the alleviative role of exogenous polyamines (PAs) applied to the medium. The assessment was based on physiological (chlorophyll a fluorescence kinetics, chlorophyll and water content) as well as biochemical (content of carbohydrates, phenols, proline, salicylic and abscisic acid, activity of low molecular weight antioxidants) parameters, measured after supplementation with PAs (putrescine, spermidine and spermine) on the 3rd, 5th and 7th day of the treatment. The results indicate that PAs ameliorate the effects of stress, indirectly and conditionally inducing stress tolerance of wheat seedlings. In contrast to the susceptible SQ1, the resistant CS cultivar activated its protective mechanisms, adjusting the degree of their activation to the level of the stress, depending on the genetic resources of the plant."},{"id":"source_13","type":"source","study":"Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses","year":2020,"doi":"10.7554/eLife.57950","url":"https://doi.org/10.7554/eLife.57950","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","cited_as":"Alsaleh 2020","excerpt":"Vaccines are powerful tools to develop immune memory to infectious diseases and prevent excess mortality. In older adults, however vaccines are generally less efficacious and the molecular mechanisms that underpin this remain largely unknown. Autophagy, a process known to prevent aging, is critical for the maintenance of immune memory in mice. Here, we show that autophagy is specifically induced in vaccine-induced antigen-specific CD8+ T cells in healthy human volunteers. In addition, reduced IFNγ secretion by RSV-induced T cells in older vaccinees correlates with low autophagy levels. We demonstrate that levels of the endogenous autophagy-inducing metabolite spermidine fall in human T cells with age. Spermidine supplementation in T cells from old donors recovers their autophagy level and function, similar to young donors' cells, in which spermidine biosynthesis has been inhibited. Finally, our data show that endogenous spermidine maintains autophagy via the translation factor eIF5A and transcription factor TFEB."},{"id":"source_14","type":"source","study":"The positive effect of spermidine in older adults suffering from dementia","year":2020,"doi":"10.1007/s00508-020-01758-y","url":"https://doi.org/10.1007/s00508-020-01758-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":"primary","cited_as":"Pekar 2020","excerpt":"The worldwide prevalence of dementia is estimated at 35.6 million and will rise to 115 million by 2050. There is therefore an urgent need for well-founded dementia diagnostics and well-researched therapeutic options. Previous studies have highlighted that spermidine has the ability to trigger the important process of dissolving amyloid-beta plaques by autophagy. They also confirmed that nutritional intervention with the natural polyamine spermidine can prevent memory loss in aging model organisms. This multicentric double-blind preliminary study focused on the effect of oral spermidine supplementation on older adults' cognitive performance. Memory tests were carried out on 85 subjects aged between 60 and 96 years in 6 nursing homes in Styria. Blood samples were taken for the determination of spermidine concentration and measurement of metabolic parameters. The results demonstrated a clear correlation between the intake of spermidine and the improvement in cognitive performance in subjects with mild and moderate dementia in the group treated with the higher spermidine dosage."},{"id":"source_15","type":"source","study":"N8‐Acetylspermidine: A Polyamine Biomarker in Ischemic Cardiomyopathy With Reduced Ejection Fraction","year":2020,"doi":"10.1161/JAHA.120.016055","url":"https://doi.org/10.1161/JAHA.120.016055","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","cited_as":"Nayak 2020","excerpt":"Background Patients with ischemic cardiomyopathy (ICM) have worse outcomes than those with coronary artery disease alone and those with non-ICM. N8-acetylspermidine (N8AS) is a polyamine that regulates ischemic cardiac apoptosis and resultant cardiac dysfunction. We hypothesized that N8AS is a mechanistic biomarker of adverse outcomes in patients with ICM. Methods and Results High-resolution plasma metabolomics profiling and mass spectrometry were used to quantitate N8AS levels in a discovery cohort of 474 patients with coronary artery disease (age: 68±11 years, 12% black, 26% women): 154 with ICM, and 320 without ICM; and in an external validation cohort of 85 patients with ICM (age: 60±12 years, 37% black, 19% women). Patients without heart failure (HF) at baseline were followed for incident HF. The association between N8AS (log 2 -transformed, standardized) and outcomes of all-cause mortality and incident HF were examined using Cox regression. N8AS was higher (10.39 [interquartile range, 7.21-17.75] versus 8.29 nmol/L [interquartile range, 5.91-11.42]; P <0.001) in patients with ICM compared with patients who had coronary artery disease without ICM."},{"id":"source_16","type":"source","study":"Plasma Polyamines and Short‐Term Adverse Outcomes Among Patients With Ischemic Stroke: A Prospective Cohort Study","year":2024,"doi":"10.1161/JAHA.124.035837","url":"https://doi.org/10.1161/JAHA.124.035837","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","cited_as":"Yang 2024","excerpt":"BACKGROUND: Polyamines have been reported to be associated with neurological function, but the associations between polyamines and the prognosis of ischemic stroke remain unclear. We aimed to prospectively investigate whether elevated plasma polyamine levels are associated with adverse outcomes in patients with ischemic stroke. METHODS AND RESULTS: Plasma polyamine levels were measured at admission in 3570 patients with acute ischemic stroke, and clinical outcomes were assessed at 3 months after stroke onset. The primary outcome was a composite outcome of death and major disability (modified Rankin Scale score≥3), and secondary outcomes included the individual outcomes of death and major disability. During a 3-month follow-up period, 877 participants (25.1%) experienced the primary outcome. Increased putrescines were associated with a decreased risk of the primary outcome (the highest versus the lowest tertile: odds ratio, 0.72 [95% CI, 0.58-0.91]; P =0.005) and major disability (odds ratio, 0.59 [95% CI, 0.47-0.74]; P <0.001). Conversely, increased spermidines were associated with an increased risk of death (hazard ratio, 1.86 [95% CI, 1.10-3.14]; P =0."},{"id":"source_17","type":"source","study":"Non-linear association between serum spermidine and mild cognitive impairment: Results from a cross-sectional and longitudinal study","year":2022,"doi":"10.3389/fnagi.2022.924984","url":"https://doi.org/10.3389/fnagi.2022.924984","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","cited_as":"Xu 2022","excerpt":"BACKGROUND: Although animal studies show that spermidine (SPD) affects cognitive function, the relevant evidence among humans is limited. We aim to examine the association between serum SPD levels and cognitive performance. MATERIALS AND METHODS: We conducted a cross-sectional and longitudinal study including a baseline and one follow-up survey. The baseline survey was conducted from June 2019 to August 2019, while the follow-up survey was conducted from June 2021 to August 2021. We analyzed 3,774 adult participants aged >35 years, who had no history of dementia. RESULTS: The mean (SD) age of the participants was 57.4 (9.8) years. Relative to the first tertile, the multivariate-adjusted ORs (95% CIs) of mild cognitive impairment (MCI) for the second and third tertile groups were 0.78 (0.65, 0.93) and 0.80 (0.67, 0.96), respectively. Restricted cubic spline models show that there is a non-linear association between SPD and MCI. In line with cross-sectional findings, the longitudinal study showed that a high SPD concentration may indicate a lower risk of MCI [ORs (95% CIs) for the third tertile of 0.62 (0.39, 0.99)]."},{"id":"source_18","type":"source","study":"5-ALA localises to the autophagy compartment and increases its fluorescence upon autophagy enhancement through caloric restriction and spermidine treatment in human glioblastoma","year":2024,"doi":"10.1016/j.bbrep.2024.101642","url":"https://doi.org/10.1016/j.bbrep.2024.101642","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","cited_as":"Fredericks 2024","excerpt":"Glioblastoma Multiforme (GBM) is the most invasive and prevalent Central Nervous System (CNS) malignancy. It is characterised by diffuse infiltrative growth and metabolic dysregulation that impairs the extent of surgical resection (EoR), contributing to its poor prognosis. 5-Aminolevulinic acid (5-ALA) fluorescence-guided surgical resection (FGR) takes advantage of the preferential generation of 5-ALA-derived fluorescence signal in glioma cells, thereby improving visualisation and enhancing the EoR. However, despite 5-ALA FGR is a widely used technique in the surgical management of malignant gliomas, the infiltrative tumour margins usually show only vague or no visible fluorescence and thus a significant amount of residual tumour tissue may hence remain in the resection cavity, subsequently driving tumour recurrence. To investigate the molecular mechanisms that govern the preferential accumulation of 5-ALA in glioma cells, we investigated the precise subcellular localisation of 5-ALA signal using Correlative Light and Electron Microscopy (CLEM) and colocalisation analyses in U118MG glioma cells."},{"id":"source_19","type":"source","study":"Functional and Biochemical Characterization of Spermidine Synthase CauSpe3 from Candidozyma auris","year":2026,"doi":"10.3390/pathogens15040432","url":"https://doi.org/10.3390/pathogens15040432","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","cited_as":"Choi 2026","excerpt":"Polyamines, putrescine, spermidine and spermine, are essential polycationic metabolites present in all eukaryotic cells, where they regulate fundamental processes including nucleic acid stabilization, translation, and stress responses. Spermidine synthase (SPDS), a member of the aminopropyltransferase (APT) family, catalyzes the transfer of an aminopropyl group from decarboxylated S-adenosylmethionine (dc-SAM) to putrescine to form spermidine. Although genomic analyses predict the presence of SPDS homologs in multiple fungal species, polyamine biosynthesis has not been experimentally characterized in the multidrug-resistant fungal pathogen Candidozyma auris . Here, we report the biochemical and functional characterization of the C. auris spermidine synthase, CauSpe3. The CauSPE3 gene complemented a Saccharomyces cerevisiae spe3Δ mutant demonstrating conserved function in vivo . Recombinant CauSpe3 was expressed in Escherichia coli , purified and analyzed using the fluorescence-based DAB-APT assay, which uses 1,2-diacetylbenzene (DAB) for polyamine detection. CauSpe3 catalyzed efficient conversion of putrescine to spermidine in the presence of dc-SAM, with K half values of 65.5 ± 7."},{"id":"source_20","type":"source","study":"High Plasma Polyamine Levels Are Associated With an Increased Risk of Poststroke Cognitive Impairment: A Multicenter Prospective Study From CATIS.","year":2025,"doi":"10.1161/jaha.124.037465","url":"https://doi.org/10.1161/jaha.124.037465","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","cited_as":"He 2025","excerpt":"BACKGROUND: Polyamines have been suggested to play pivotal roles in ischemic stroke and neurodegenerative disorders, but the associations of plasma polyamines with poststroke cognitive impairment (PSCI) remain unclear. We aimed to prospectively investigate the associations of plasma putrescine, spermidine, and spermine with PSCI among patients with ischemic stroke in a multicenter cohort study. METHODS AND RESULTS: We measured plasma polyamine levels at baseline among 619 patients with ischemic stroke from a preplanned ancillary study of CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). We used the Mini-Mental State Examination and Montreal Cognitive Assessment to evaluate cognitive function at 3-month follow-up after ischemic stroke, and PSCI was defined as Mini-Mental State Examination score <27 or Montreal Cognitive Assessment score <25. According to the Mini-Mental State Examination score, plasma polyamines were positively associated with PSCI. The adjusted odds ratios of PSCI for the highest versus lowest quartile of putrescine, spermidine, and spermine were 1.81 (95% CI, 1.09-3.00), 1.81 (95% CI, 1.09-3.01), and 1.92 (95% CI, 1.15-3.20), respectively."},{"id":"source_21","type":"source","study":"Targeting Polyamine Metabolism in Colorectal Cancer: Apigenin Dismantles the HIF-1α/SMOX Positive Feedback Loop to Suppress Tumor Progression","year":2026,"doi":"10.3390/ijms27073261","url":"https://doi.org/10.3390/ijms27073261","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","cited_as":"Zhang 2026","excerpt":"Tumor microenvironments, particularly hypoxia and inflammation, heavily influence colorectal cancer (CRC) pathogenesis by altering polyamine metabolism. Identifying natural compounds targeting these vulnerabilities remains critical. Integrating untargeted metabolomics, network pharmacology, and a human endogenous metabolite library screen, we identified apigenin (API) as a potent anti-CRC candidate. API significantly inhibited the proliferation, migration, and invasion of RKO and HCT116 cells in vitro and suppressed xenograft tumor growth in vivo. Crucially, high-throughput screening revealed that polyamines rescued CRC cells from API-induced cytotoxicity. Mechanistically, API exerts its effects by dismantling a newly identified HIF-1α/SMOX positive feedback loop. In CRC, HIF-1α transcriptionally activates spermine oxidase (SMOX), while SMOX-driven polyamine metabolism fuels the TLR4/MyD88 inflammatory cascade to continuously stabilize HIF-1α. API acts as a \"circuit breaker\" for this axis, significantly reducing the spermidine/spermine ratio and downregulating inflammatory signaling."},{"id":"source_22","type":"source","study":"Spermidine improve high copper diet-induced intestinal oxidative stress and microbiota community composition.","year":2026,"doi":"10.1080/10715762.2026.2625094","url":"https://doi.org/10.1080/10715762.2026.2625094","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","cited_as":"Qi 2026","excerpt":"High copper diet intake detriment animal health and livestock profitability. As a key polyamine, spermidine modulates critical physiological processes, include regulating autophagy and oxidative stress. However, the effect of spermidine in mitigating intestinal oxidative stress triggered by high copper diet has yet to be fully elucidated. In this study, eight-week male C57BL/6J mice were fed either a normal diet or a high-copper diet, supplemented with spermidine through water alone or in combination. The intestinal morphology was analyzed using HE staining, intestinal index, antioxidant capacity, SIgA, the content of copper ion, serum IgA, IgG and D-LA were detection. 16S rRNA was used to assess intestinal microbiota composition. The results showed that high copper diet intake disrupted intestinal morphology, elevated jejunum copper levels by 97% ( p < 0.05), increased MDA by 31% and T-AOC by 54% in the duodenum ( p < 0.05). Similarly, jejunum MDA increase by 49% and SOD rose by18% ( p < 0.05). However, compared to CuSO 4 group, spermidine co-treatment improved duodenum villus-crypt ratio by 37% and enhanced serum IgG and IgA concentrations by 16% and 33% ( p < 0.05)."},{"id":"source_23","type":"source","study":"Spermidine and spermine in elderly patients with coronary artery disease: a cross-sectional study of dietary intake and plasma and skeletal muscle concentrations.","year":2026,"doi":"10.1016/j.clnu.2026.106651","url":"https://doi.org/10.1016/j.clnu.2026.106651","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","cited_as":"Thorup 2026","excerpt":"BACKGROUND AND AIMS: Spermidine, a polyamine abundant in plant-based and fermented foods, has been associated with reduced cardiovascular and all-cause mortality. However, whether dietary spermidine intake is reflected in circulating and skeletal muscle concentrations remains unclear, and tissue data are scarce. We therefore investigated the associations between dietary spermidine intake and spermidine concentrations in plasma and skeletal muscle in elderly patients with coronary artery disease. METHODS: We examined dietary spermidine and spermine intake using a food frequency questionnaire, and plasma and skeletal muscle concentrations by targeted LC-MS/MS. Associations between intake, plasma and skeletal muscle concentrations were assessed using multivariable linear regression models adjusted for age, sex, body mass index, educational level, total daily energy intake, serum creatinine, medical treatment and comorbidities. RESULTS: A total of 192 patients with coronary artery disease were included (age 72 years [68-76] and 80% male). Median dietary spermidine intake was 11.5 mg/day [9.5-14.3] (n = 184). Median spermidine concentrations were 21.0 ng/mL [16.2-27."},{"id":"source_24","type":"source","study":"Effects of Spermidine-Rich Rice Germ Extract Supplement on Biomarkers of Healthy Aging and Autophagy-Proof-of-Concept Pilot Study.","year":2025,"doi":null,"url":"https://pubmed.ncbi.nlm.nih.gov/40862848/","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","cited_as":"Bruno 2025","excerpt":"BACKGROUND: Although epidemiological and preclinical research suggests that the polyamine spermidine improves the efficiency of autophagy, human clinical research demonstrating a specific dose of any source of spermidine capable of increasing biomarkers of autophagy is lacking. PRIMARY STUDY OBJECTIVE: The study aimed to examine the effects of spermidine from Miricell™ rice germ extract (Nutraland USA) on biomarkers/indices of autophagy, neuroprotection, and cardiometabolic health, as well as safety and adverse events. METHODS/DESIGN: This 56-day study was conducted as a single-blinded, interventional, parallel-group, pilot trial. Vitals, diet records, and protocol compliance were recorded at weeks 0 and 8. Blood draws for cardiometabolic markers and adverse event monitoring took place at screening and weeks 0 and 8. SETTING: Conducted at a clinical research laboratory in Ohio. PARTICIPANTS: Twelve (N=12) healthy men and women (age: 54.5 ± 7.9 years). INTERVENTION: Random assignment to 1.5 mg or 3.3 mg of spermidine daily from Miricell™ rice germ extract (Nutraland USA)."},{"id":"source_25","type":"source","study":"Spermidine induces cytoprotective autophagy of female germline stem cells in vitro and ameliorates aging caused by oxidative stress through upregulated sequestosome-1/p62 expression","year":2021,"doi":"10.1186/s13578-021-00614-4","url":"https://doi.org/10.1186/s13578-021-00614-4","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","cited_as":"Yuan 2021","excerpt":"BACKGROUND: Autophagy is required for oogenesis and plays a critical role in response to aging caused by oxidative stress. However, there have been no reports on regulation of cytoprotective autophagy in female germline stem cells (FGSCs) in response to aging caused by oxidative stress. RESULTS: We found that Spermidine (SPD) significantly increased protein expression of autophagy markers microtubule-associated protein 1 light chain 3 beta-II (MAP1LC3B-II/LC3B-II) and sequestosome-1/p62 (SQSTM1/p62), and evoked autophagic flux in FGSCs. Moreover, SPD increased the number and viability of FGSCs in vitro. Further, we found that SPD significantly reduced basal or hydrogen peroxide (H 2 O 2 )-induced up-regulated protein expression of the aging markers, cyclin dependent kinase inhibitor 2A (p16/CDKN2A) and tumor protein 53 (p53). After knockdown of p62 in FGSCs, p16 protein levels were significant higher compared with controls. However, protein p16 levels were not significantly changed in p62 knockdown FGSCs with SPD treatment compared with without SPD."},{"id":"source_26","type":"source","study":"Treatment of peri-implant mucositis using spermidine and calcium chloride as local adjunctive delivery to non-surgical mechanical debridement: a double-blind randomized controlled clinical trial.","year":2024,"doi":"10.1007/s00784-024-05924-8","url":"https://doi.org/10.1007/s00784-024-05924-8","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","cited_as":"Iorio-Siciliano 2024","excerpt":"OBJECTIVES: To evaluate the effects of non-surgical mechanical debridement with or without adjunctive application of a gel with spermidine and sodium hyaluronate associated to a sealing gel (i.e. calcium chloride) in the treatment of peri-implant mucositis (PiM). MATERIALS AND METHODS: Forty patients with one implant with PiM were randomly allocated in test and control groups. Test implants were treated with non-surgical mechanical debridement and local unique application of spermidine and calcium chloride gel while control implants were treated using non-surgical mechanical debridement alone. The primary outcome was BOP change. FMPS, FMBS and PD were also assessed. For an Implant the presence of a single bleeding spot (1 site/implant without a continuous line or profuse bleeding) was considered as complete disease resolution. RESULTS: After 3 months, a statistically significant improvement of all parameters were recorded in each group (p < 0.05). However, no statistically significant differences were found between test and control procedures (p > 0.05). At 3 months, 85% of test implants and 70% of control implants resulted in disease resolution."},{"id":"source_27","type":"source","study":"Supplementation of spermidine at 40 mg/day has minimal effects on circulating polyamines: An exploratory double-blind randomized controlled trial in older men.","year":2024,"doi":"10.1016/j.nutres.2024.09.012","url":"https://doi.org/10.1016/j.nutres.2024.09.012","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","cited_as":"Keohane 2024","excerpt":"This study represents the first investigation into the safety of a novel, high-purity spermidine trihydrochloride supplement (hpSPD) in humans. Spermidine, a natural compound found in various foods, has demonstrated potential health benefits in animal and epidemiological studies. However, evidence from clinical trials and safety evaluations of spermidine supplements is limited because pure spermidine for human administration has not been available. In this randomized, double-blind, within-subject and placebo-controlled trial, 37 healthy men (age 50-70 years; body mass index, 18.5-28 kg/m 2 ) were administered either hpSPD or a placebo. We hypothesized that 7-day and 28-day dosing of 40 mg/day of hpSPD would have minimal effects on safety, although metabolic and polyamine homeostasis has not previously been examined at this dosage level. Consistent with our hypothesis, 40 mg/day hpSPD did not result in any significant changes in clinical, lipids, chemistry, or hematological parameters compared to placebo. Compliance was high, and no study product-related adverse events were reported."},{"id":"source_28","type":"source","study":"The role of spermidine in plants and humans: a pathway from climate change adaptation to health benefits","year":2026,"doi":"10.1038/s41538-025-00695-2","url":"https://doi.org/10.1038/s41538-025-00695-2","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","cited_as":"Blagojevic 2026","excerpt":"Growing demands for healthier diets are driving agricultural and food scientists to develop climate-resilient crops and food systems that ensure nutritionally effective food. Beyond providing basic energy requirements, nutrients may actively influence human physiology and health. One such molecule, spermidine, a polyamine abundant in wheat and soybean, has attracted particular interest. From the aspect of human health, spermidine is mainly studied for healthy ageing properties and has been associated with cardioprotective, neuroprotective, and anti-cancerogenic effects. On the other hand, being present in all plants, spermidine is essential for growth, development, and stress adaptation. Endogenously or when exogenously applied, spermidine can help plants adapt to harsh climate change conditions. Bringing together current knowledge on the significance of spermidine in both plants and humans, this review aims to trace its journey From Farm to Pharm, highlighting its importance for sustainable crop production, improved nutrition, and emerging pharmacological applications."},{"id":"source_29","type":"source","study":"Unraveling the role of polyamine metabolism in postoperative delirium: insights into biochemical mechanisms and biomarker potential","year":2026,"doi":"10.1038/s41514-025-00324-y","url":"https://doi.org/10.1038/s41514-025-00324-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":"primary","cited_as":"Saiyed 2026","excerpt":"Postoperative delirium (POD) is a common complication in older surgical patients, linked to long-term cognitive decline and progression to dementia, yet its mechanisms remain unclear. We investigated arginine-related metabolites (ARMs) in cerebrospinal fluid (CSF) from 248 patients undergoing elective-surgery: 25 developed POD. Targeted mass spectrometry, gene expression profiling, and machine learning were applied to identify metabolic predictors. POD patients showed significant correlations with citrulline, ornithine, and glutamine, while models highlighted glutamine, glutamic acid, putrescine, N1-acetylspermidine, and spermidine as key biomarkers, achieving >77% predictive accuracy. Cluster and pathway analyses revealed POD-specific shifts in GABA synthesis and polyamine metabolism, contrasting with urea cycle dominance in non-POD cases. Associations persisted after adjusting for age and CSF Aβ42. Preoperative profiles in polyamine metabolism, ammonia detoxification, and neurotransmitter regulation suggest underlying neuroinflammatory and oxidative stress vulnerabilities that reduce resilience."},{"id":"source_30","type":"source","study":"Loss-of-function variant in spermidine/spermine N1-acetyl transferase like 1 ( SATL1 ) gene as an underlying cause of autism spectrum disorder","year":2024,"doi":"10.1038/s41598-024-56253-5","url":"https://doi.org/10.1038/s41598-024-56253-5","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","cited_as":"Alayoubi 2024","excerpt":"Autism spectrum disorder (ASD) is a complicated, lifelong neurodevelopmental disorder affecting verbal and non-verbal communication and social interactions. ASD signs and symptoms appear early in development before the age of 3 years. It is unlikely for a person to acquire autism after a period of normal development. However, we encountered an 8-year-old child who developed ASD later in life although his developmental milestones were normal at the beginning of life. Sequencing the complete coding part of the genome identified a hemizygous nonsense mutation (NM_001367857.2):c.1803C>G; (p.Tyr601Ter) in the gene (SATL1) encoding spermidine/spermine N1-acetyl transferase like 1. Screening an ASD cohort of 28 isolated patients for the SATL1 gene identified another patient with the same variant. Although SATL1 mutations have not been associated with any human diseases, our data suggests that a mutation in SATL1 is the underlying cause of ASD in our cases. In mammals, mutations in spermine synthase (SMS), an enzyme needed for the synthesis of spermidine polyamine, have been reported in a syndromic form of the X-linked mental retardation."},{"id":"source_31","type":"source","study":"Absorption, anti-inflammatory, antioxidant, and cardioprotective impacts of a novel fasting mimetic containing spermidine, nicotinamide, palmitoylethanolamide, and oleoylethanolamide: A pilot dose-escalation study in healthy young adult men.","year":2024,"doi":"10.1016/j.nutres.2024.10.006","url":"https://doi.org/10.1016/j.nutres.2024.10.006","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","cited_as":"Rhodes 2024","excerpt":"This pilot dose-escalation study evaluated the absorption and metabolism of a novel fasting mimetic formulation containing spermidine, nicotinamide, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) taken as oral supplements in young adults. Five healthy men consumed a standardized breakfast, followed by control (wheat flour) or low, medium, or high doses of supplements containing spermidine, nicotinamide, PEA, and OEA 2 hours later. Blood was drawn at 0, 1, 2, and 4 hours after the supplement (2, 3, 4, and 6 hours postprandial). Plasma concentrations of spermidine, 1-methylnicotinamide, PEA and OEA were quantified by liquid chromatography-mass spectrometry. The secretion of tumor necrosis factor alpha and production of reactive oxygen species by stimulated macrophages incubated with plasma, and cholesterol efflux capacity of plasma were analyzed. Plasma 1-methylnicotinamide, PEA, and OEA concentrations increased after supplement intake (P < .05). Spermidine concentrations decreased in the control arm (P < .05) but not the supplement arms."},{"id":"source_32","type":"source","study":"SPERMIDINE TOXICITY IN MITOCHONDRIAL DNA-DEFICIENT SACCHAROMYCES CEREVISIAE","year":2022,"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":"review-level","cited_as":"SPERMIDINE TOXICITY in MITOCHONDRIAL 2022","excerpt":"Over the last 20 years or so, a number of drugs have been found toextend lifespan in model organisms. However, we found thatspermidine significantly shortened lifespan in these cells, decreasing the medianlifespan from 6 days to 4 days."},{"id":"source_33","type":"source","study":"The Effect of Foliar Application of Salicylic Acid, Spermidine and Sodium Nitroprusside on some Growth and Flowering Characteristics, Photosynthetic Pigments and Vase Life of Lisianthus ‘Mariachi Blue’","year":2023,"doi":"10.22067/jhs.2022.74334.1118","url":"https://doi.org/10.22067/jhs.2022.74334.1118","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","cited_as":"Effect of Foliar Application 2023","excerpt":"The treatments were included spermidine at concentrations of 0.5, 1 and 2 mM, salicylic acid at concentrations of 0.5, 1 and 1.5 mM, sodium nitroprusside at concentrations of 50, 100 and 200 μM and control (without any application of growth regulators) as foliar application at intervals of 15 days for 2 months."},{"id":"source_34","type":"source","study":"Improving Vaccination in Older Adults by Inducing Autophagy With Spermidine","year":2023,"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":"review-level","cited_as":"Improving Vaccination in Older 2023","excerpt":"We will give the nutraceutical spermidine to human volunteers aged \\>65 years either during or after vaccination against SARS-CoV-2 or influenza to test improvement of vaccine responses, immune senescence and inflamm-aging."},{"id":"source_35","type":"source","study":"Metabolic Responses to Spermidine Supplementation.","year":2023,"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":"review-level","cited_as":"Metabolic Responses to Spermidine 2023","excerpt":"To date, human research studies utilised extracts containing low levels of spermidine (\\< 10%) and multiple other constituents, but this study will use pure spermidine to explore relevant mechanisms of action, biological effects, and identify potential biomarkers of positive biological effects."},{"id":"source_36","type":"source","study":"Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline","year":2018,"doi":"10.18632/aging.101354","url":"https://doi.org/10.18632/aging.101354","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","cited_as":"Schwarz 2018","excerpt":"Supplementation of spermidine, an autophagy-inducing agent, has been shown to protect against neurodegeneration and cognitive decline in aged animal models. The present translational study aimed to determine safety and tolerability of a wheat germ extract containing enhanced spermidine concentrations. In a preclinical toxicity study, supplementation of spermidine using this extract did not result in morbidities or changes in behavior in BALBc/Rj mice during the 28-days repeated-dose tolerance study. Post mortem examination of the mice organs showed no increase in tumorigenic and fibrotic events. In the human cohort (participants with subjective cognitive decline, n=30, 60 to 80 years of age), a 3-month randomized, placebo-controlled, double-blind Phase II trial was conducted with supplementation of the spermidine-rich plant extract (dosage: 1.2 mg/day). No differences were observed between spermidine and placebo-treated groups in vital signs, weight, clinical chemistry and hematological parameters of safety, as well as in self-reported health status at the end of intervention. Compliance rates above 85% indicated excellent tolerability."},{"id":"source_37","type":"source","study":"Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)—study protocol for a randomized controlled trial","year":2019,"doi":"10.1186/s13195-019-0484-1","url":"https://doi.org/10.1186/s13195-019-0484-1","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","cited_as":"Wirth 2019","excerpt":"BACKGROUND: Given the global increase in the aging population and age-related diseases, the promotion of healthy aging is one of the most crucial public health issues. This trial aims to contribute to the establishment of effective approaches to promote cognitive and brain health in older individuals with subjective cognitive decline (SCD). Presence of SCD is known to increase the risk of objective cognitive decline and progression to dementia due to Alzheimer's disease. Therefore, it is our primary goal to determine whether spermidine supplementation has a positive impact on memory performance in this at-risk group, as compared with placebo. The secondary goal is to examine the effects of spermidine intake on other neuropsychological, behavioral, and physiological parameters. METHODS: The SmartAge trial is a monocentric, randomized, double-blind, placebo-controlled phase IIb trial. The study will investigate 12 months of intervention with spermidine-based nutritional supplementation (target intervention) compared with 12 months of placebo intake (control intervention)."},{"id":"source_38","type":"source","study":"Spermidine restores dysregulated autophagy and polyamine synthesis in aged and osteoarthritic chondrocytes via EP300","year":2018,"doi":"10.1038/s12276-018-0149-3","url":"https://doi.org/10.1038/s12276-018-0149-3","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","cited_as":"Sacitharan 2018","excerpt":"Ageing is the primary risk factor for osteoarthritis (OA). A decline in the ageing-associated process of autophagy is suggested as a potential contributor to OA development. Polyamines such as spermidine decrease during ageing, contributing to impaired autophagy and reduced cellular function. However, the role of polyamines and their effect on the regulatory mechanism governing autophagy in aged and arthritic cartilage tissue has not been established. Elucidating if polyamine regulation of autophagy is impaired during ageing and OA in chondrocytes may lead to improved treatment approaches to protect against cartilage degradation. Our results indicate that polyamine synthesis was decreased in aged and OA cartilage, along with reduced autophagy activity, evidenced by decreased autophagy-related gene and protein expression and autophagosome formation. Importantly, spermidine treatment increased the expression of the acetyltransferase EP300, which binds to crucial autophagy proteins, Beclin1 and LC3, and elevates chondrocyte autophagy. Our data indicate spermidine prevents the ageing- and OA-related decrease in autophagy and may protect against OA development."},{"id":"source_39","type":"source","study":"Polyamines in Food","year":2019,"doi":"10.3389/fnut.2019.00108","url":"https://doi.org/10.3389/fnut.2019.00108","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","cited_as":"Munoz-Esparza 2019","excerpt":"The polyamines spermine, spermidine, and putrescine are involved in various biological processes, notably in cell proliferation and differentiation, and also have antioxidant properties. Dietary polyamines have important implications in human health, mainly in the intestinal maturation and in the differentiation and development of immune system. The antioxidant and anti-inflammatory effect of polyamine can also play an important role in the prevention of chronic diseases such as cardiovascular diseases. In addition to endogenous synthesis, food is an important source of polyamines. Although there are no recommendations for polyamine daily intake, it is known that in stages of rapid cell growth (i.e., in the neonatal period), polyamine requirements are high. Additionally, de novo synthesis of polyamines tends to decrease with age, which is why their dietary sources acquire a greater importance in an aging population. Polyamine daily intake differs among to the available estimations, probably due to different dietary patterns and methodologies of data collection. Polyamines can be found in all types of foods in a wide range of concentrations."},{"id":"source_40","type":"source","study":"The effect of spermidine on memory performance in older adults at risk for dementia: A randomized controlled trial.","year":2018,"doi":"10.1016/j.cortex.2018.09.014","url":"https://doi.org/10.1016/j.cortex.2018.09.014","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","cited_as":"Wirth 2018","excerpt":"INTRODUCTION: Nutritional intervention with the natural polyamine spermidine, an autophagy-enhancing agent, can prevent memory loss in aging model organisms. This is the first human study to evaluate the impact of spermidine supplementation on memory performance in older adults at risk for the development of Alzheimer's disease. METHODS: Cognitively intact participants with subjective cognitive decline (n = 30, 60-80 years of age) were included in this three-months, randomized, placebo-controlled, double-blind Phase IIa pilot trial with a spermidine-rich plant extract supplement. Effects of intervention were assessed using the behavioral mnemonic similarity task, measured at baseline and post-intervention visits. Data analysis was focused on reporting and interpreting effectiveness based on effect sizes. RESULTS: Memory performance was moderately enhanced in the spermidine group compared with placebo at the end of intervention [contrast mean = .17, 95% confidence interval (CI): -.01, .35, Cohen's d = .77, 95% CI: 0, 1.53]. Mnemonic discrimination ability improved in the spermidine-treated group with a medium effect size (mean difference = -.11, 95% CI: -.19, -.03, Cohen's d = ."},{"id":"source_41","type":"source","study":"Consumption effect of a synbiotic beverage made from soy and yacon extracts containing Bifidobacterium animalis ssp. lactis BB-12 on the intestinal polyamine concentrations in elderly individuals.","year":2017,"doi":"10.1016/j.foodres.2017.06.005","url":"https://doi.org/10.1016/j.foodres.2017.06.005","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","cited_as":"Manzoni 2017","excerpt":"This study aimed to investigate the effect of a synbiotic beverage made from soy and yacon (Smallanthus sonchifolius) extracts containing Bifidobacterium animalis ssp. lactis BB-12 on healthy elderly individuals' intestinal polyamine concentrations. A randomized, double-blinded, placebo-controlled trial has been conducted with twenty-nine volunteers (over 65years of age) who either had a daily intake of 150mL of synbiotic (synbiotic group - S) or placebo (placebo group - P) beverages. Both had the same nutrient composition, except that a probiotic culture was added to the synbiotic beverage. Total experiment time was 8weeks, which was divided into 3 consecutive phases: a prefeeding period (2weeks), followed by a feeding period (4weeks) and a postfeeding period (2weeks). Stool samples were collected at 3 time periods. Fecal concentrations of polyamines, putrescine (PUT), cadaverine (CAD) and spermidine (SPD) that were obtained during the synbiotic and placebo consumption period were significantly higher (p<0.05) than those found during the pre-consumption baseline level period."},{"id":"source_42","type":"source","study":"Autophagy-Enhancers to Reduce Sleep Disturbances","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":"review-level","cited_as":"Autophagy-Enhancers to Reduce Sleep n.d.","excerpt":"In this randomized, double-blind, placebo-controlled trial, 76 participants aged 55 to 70 years with MCI will receive either spermidine (6 mg/day) or a placebo for 12 weeks."}],"edges":[{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_1","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_2","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_3","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_4","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_5","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_6","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_7","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_8","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_9","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_10","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_11","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_12","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_13","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_14","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_15","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_16","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_17","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_18","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_19","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_20","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_21","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_22","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_23","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_24","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_25","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_26","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_27","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_28","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_29","type":"contains_claim"},{"from":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","to":"claim_30","type":"contains_claim"}],"screening":{"identified":42,"screened":42,"excluded":0,"included":42,"included_or_retained":42,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"42 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":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","screening":{"identified":42,"screened":42,"excluded":0,"included":42,"included_or_retained":42,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"42 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":["Positive study-level signals are summarized in the immune and inflammation outcome class; null signals are summarized in the contextual adjacent evidence, mechanism, dosing and pharmacokinetics, longevity, cardiometabolic, deficiency prevalence, muscle function, and skeletal, fracture, and bone outcome classes; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the safety and comorbidity and frailty outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","The conclusion is that Spermidine supplementation 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.","The endpoint scope of the corpus is narrow and skewed toward mechanism, biomarker, and short-term proxy measures. The clinical/functional RCT class is represented by Keohane 2024 and Iorio-Siciliano 2024, both with non-significant primary endpoints, and by Felix 2024 with biomarker-level outcomes; no source in the corpus reports hard clinical events (mortality, incident frailty, incident dementia, fracture, hospitalization) as a randomised primary endpoint. Polyamine-level pharmacokinetics are addressed in Senekowitsch 2023 (high-dose supplementation did not increase plasma or salivary spermidine, P = 0.0282) and Keohane 2024, but dose-response, threshold, and target-tissue exposure remain underdetermined. Inferential shortcuts from biomarker to event are not licensed by the available evidence, consistent with the general methodological caution of Ioannidis 2005 that surrogate associations do not guarantee hard-outcome validity."]}},{"name":"evidence_table.csv","media_type":"text/csv","content":"study,population,intervention_or_exposure,comparator,endpoint,effect,risk_of_bias,directness\r\nSpermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSpermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nWhole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nHigh-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSpermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"POLYamine treatment in elderly patients with Coronary Artery Disease (POLYCAD): study protocol for a Danish randomised, double-blind, placebo-controlled trial of spermidine treatment versus placebo\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nDysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Human Supplementation with AM3, Spermidine, and Hesperidin Enhances Immune Function, Decreases Biological Age, and Improves Oxidative–Inflammatory State: A Randomized Controlled Trial\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSpermine and spermidine modulate T-cell function in older adults with and without cognitive decline ex vivo,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nEffects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSpermidine improves seed viability in Allium mongolicum by regulating AmCS-mediated metabolic and antioxidant networks,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nExogenous Polyamines Only Indirectly Induce Stress Tolerance in Wheat Growing in Hydroponic Culture under Polyethylene Glycol-Induced Osmotic Stress,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAutophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nThe positive effect of spermidine in older adults suffering from dementia,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nN8‐Acetylspermidine: A Polyamine Biomarker in Ischemic Cardiomyopathy With Reduced Ejection Fraction,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nPlasma Polyamines and Short‐Term Adverse Outcomes Among Patients With Ischemic Stroke: A Prospective Cohort Study,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nNon-linear association between serum spermidine and mild cognitive impairment: Results from a cross-sectional and longitudinal study,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n5-ALA localises to the autophagy compartment and increases its fluorescence upon autophagy enhancement through caloric restriction and spermidine treatment in human glioblastoma,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nFunctional and Biochemical Characterization of Spermidine Synthase CauSpe3 from Candidozyma auris,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nHigh Plasma Polyamine Levels Are Associated With an Increased Risk of Poststroke Cognitive Impairment: A Multicenter Prospective Study From CATIS.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nTargeting Polyamine Metabolism in Colorectal Cancer: Apigenin Dismantles the HIF-1α/SMOX Positive Feedback Loop to Suppress Tumor Progression,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSpermidine improve high copper diet-induced intestinal oxidative stress and microbiota community composition.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSpermidine and spermine in elderly patients with coronary artery disease: a cross-sectional study of dietary intake and plasma and skeletal muscle concentrations.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nEffects of Spermidine-Rich Rice Germ Extract Supplement on Biomarkers of Healthy Aging and Autophagy-Proof-of-Concept Pilot Study.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSpermidine induces cytoprotective autophagy of female germline stem cells in vitro and ameliorates aging caused by oxidative stress through upregulated sequestosome-1/p62 expression,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nTreatment of peri-implant mucositis using spermidine and calcium chloride as local adjunctive delivery to non-surgical mechanical debridement: a double-blind randomized controlled clinical trial.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSupplementation of spermidine at 40 mg/day has minimal effects on circulating polyamines: An exploratory double-blind randomized controlled trial in older men.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nThe role of spermidine in plants and humans: a pathway from climate change adaptation to health benefits,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nUnraveling the role of polyamine metabolism in postoperative delirium: insights into biochemical mechanisms and biomarker potential,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nLoss-of-function variant in spermidine/spermine N1-acetyl transferase like 1 ( SATL1 ) gene as an underlying cause of autism spectrum disorder,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Absorption, anti-inflammatory, antioxidant, and cardioprotective impacts of a novel fasting mimetic containing spermidine, nicotinamide, palmitoylethanolamide, and oleoylethanolamide: A pilot dose-escalation study in healthy young adult men.\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSPERMIDINE TOXICITY IN MITOCHONDRIAL DNA-DEFICIENT SACCHAROMYCES CEREVISIAE,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\n\"The Effect of Foliar Application of Salicylic Acid, Spermidine and Sodium Nitroprusside on some Growth and Flowering Characteristics, Photosynthetic Pigments and Vase Life of Lisianthus ‘Mariachi Blue’\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nImproving Vaccination in Older Adults by Inducing Autophagy With Spermidine,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nMetabolic Responses to Spermidine Supplementation.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSafety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nEffects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)—study protocol for a randomized controlled trial,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSpermidine restores dysregulated autophagy and polyamine synthesis in aged and osteoarthritic chondrocytes via EP300,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nPolyamines in Food,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nThe effect of spermidine on memory performance in older adults at risk for dementia: A randomized controlled trial.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nConsumption effect of a synbiotic beverage made from soy and yacon extracts containing Bifidobacterium animalis ssp. lactis BB-12 on the intestinal polyamine concentrations in elderly individuals.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nAutophagy-Enhancers to Reduce Sleep Disturbances,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\n"},{"name":"risk_of_bias.json","media_type":"application/json","content":{"publication_id":"0326ee6c-57b7-4644-a7c4-9c81b0c5541c","method_note":"Risk-of-bias fields are surfaced when supplied by the submitting agent; otherwise marked as not appraised 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