source · application/json
source_81d393562e384ce8
sha256 e6be6de1ede5cf7c7bb9f8deaa0c0dce92571cb2a7e7f762182baa245e727d69
by researka:v2 · 2026-06-24 03:26:22.979809+04:00
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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.", "type": "claim"}, {"id": "claim_2", "text": "This paper synthesizes evidence on Spermidine supplementation across 42 included source papers and 1250 high-confidence extracted claims.", "type": "claim"}, {"id": "claim_3", "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.", "type": "claim"}, {"id": "claim_4", "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.", "type": "claim"}, {"id": "claim_5", "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.", "type": "claim"}, {"id": "claim_6", "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`.", "type": "claim"}, {"id": "claim_7", "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.", "type": "claim"}, {"id": "claim_8", "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.", "type": "claim"}, {"id": "claim_9", "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.", "type": "claim"}, {"id": "claim_10", "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.", "type": "claim"}, {"id": "claim_11", "text": "| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |", "type": "claim"}, {"id": "claim_12", "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 |", "type": "claim"}, {"id": "claim_13", "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.", "type": "claim"}, {"id": "claim_14", "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.", "type": "claim"}, {"id": "claim_15", "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.", "type": "claim"}, {"id": "claim_16", "text": "3 included sources were assigned to this outcome class. Directional coding: null=1, positive=2. Directness coding: direct=1, indirect=2.", "type": "claim"}, {"id": "claim_17", "text": "3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: mechanistic=3.", "type": "claim"}, {"id": "claim_18", "text": "2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: review=2.", "type": "claim"}, {"id": "claim_19", "text": "2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=1, review=1.", "type": "claim"}, {"id": "claim_20", "text": "2 included sources were assigned to this outcome class. Directional coding: null=1, unclear=1. Directness coding: indirect=1, mechanistic=1.", "type": "claim"}, {"id": "claim_21", "text": "1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: direct=1.", "type": "claim"}, {"id": "claim_22", "text": "1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.", "type": "claim"}, {"id": "claim_23", "text": "1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: review=1.", "type": "claim"}, {"id": "claim_24", "text": "1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: direct=1.", "type": "claim"}, {"id": "claim_25", "text": "Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.", "type": "claim"}, {"id": "claim_26", "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.", "type": "claim"}, {"id": "claim_27", "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.", "type": "claim"}, {"id": "claim_28", "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.", "type": "claim"}, {"id": "claim_29", "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.", "type": "claim"}, {"id": "claim_30", "text": "Across 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.", "type": "claim"}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3390/cells10010095", "effect": "not extracted", "endpoint": "not extracted", "id": "source_1", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "type": "source", "url": "https://doi.org/10.3390/cells10010095", "year": 2021}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1007/s12035-026-05763-6", "effect": "not extracted", "endpoint": "not extracted", "id": "source_2", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "type": "source", "url": "https://doi.org/10.1007/s12035-026-05763-6", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3390/biomedicines11051403", "effect": "not extracted", "endpoint": "not extracted", "id": "source_3", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "type": "source", "url": "https://doi.org/10.3390/biomedicines11051403", "year": 2023}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.3390/nu15081852", "effect": "not extracted", "endpoint": "not extracted", "id": "source_4", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "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", "type": "source", "url": "https://doi.org/10.3390/nu15081852", "year": 2023}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1111/acel.70545", "effect": "not extracted", "endpoint": "not extracted", "id": "source_5", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "type": "source", "url": "https://doi.org/10.1111/acel.70545", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1186/s13063-025-09176-z", "effect": "not extracted", "endpoint": "not extracted", "id": "source_6", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "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", "type": "source", "url": "https://doi.org/10.1186/s13063-025-09176-z", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1371/journal.pmed.1003012", "effect": "not extracted", "endpoint": "not extracted", "id": "source_7", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study", "type": "source", "url": "https://doi.org/10.1371/journal.pmed.1003012", "year": 2020}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3390/antiox13111391", "effect": "not extracted", "endpoint": "not extracted", "id": "source_8", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Human Supplementation with AM3, Spermidine, and Hesperidin Enhances Immune Function, Decreases Biological Age, and Improves Oxidative–Inflammatory State: A Randomized Controlled Trial", "type": "source", "url": "https://doi.org/10.3390/antiox13111391", "year": 2024}, {"comparator": "not extracted", "directness": "primary", "doi": "10.18632/aging.103527", "effect": "not extracted", "endpoint": "not extracted", "id": "source_9", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Spermine and spermidine modulate T-cell function in older adults with and without cognitive decline ex vivo", "type": "source", "url": "https://doi.org/10.18632/aging.103527", "year": 2020}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1001/jamanetworkopen.2022.13875", "effect": "not extracted", "endpoint": "not extracted", "id": "source_10", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline", "type": "source", "url": "https://doi.org/10.1001/jamanetworkopen.2022.13875", "year": 2022}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3389/fpls.2025.1683362", "effect": "not extracted", "endpoint": "not extracted", "id": "source_11", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Spermidine improves seed viability in Allium mongolicum by regulating AmCS-mediated metabolic and antioxidant networks", "type": "source", "url": "https://doi.org/10.3389/fpls.2025.1683362", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3390/life10080151", "effect": "not extracted", "endpoint": "not extracted", "id": "source_12", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Exogenous Polyamines Only Indirectly Induce Stress Tolerance in Wheat Growing in Hydroponic Culture under Polyethylene Glycol-Induced Osmotic Stress", "type": "source", "url": "https://doi.org/10.3390/life10080151", "year": 2020}, {"comparator": "not extracted", "directness": "primary", "doi": "10.7554/eLife.57950", "effect": "not extracted", "endpoint": "not extracted", "id": "source_13", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses", "type": "source", "url": "https://doi.org/10.7554/eLife.57950", "year": 2020}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1007/s00508-020-01758-y", "effect": "not extracted", "endpoint": "not extracted", "id": "source_14", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "The positive effect of spermidine in older adults suffering from dementia", "type": "source", "url": "https://doi.org/10.1007/s00508-020-01758-y", "year": 2020}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1161/JAHA.120.016055", "effect": "not extracted", "endpoint": "not extracted", "id": "source_15", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "N8‐Acetylspermidine: A Polyamine Biomarker in Ischemic Cardiomyopathy With Reduced Ejection Fraction", "type": "source", "url": "https://doi.org/10.1161/JAHA.120.016055", "year": 2020}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1161/JAHA.124.035837", "effect": "not extracted", "endpoint": "not extracted", "id": "source_16", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Plasma Polyamines and Short‐Term Adverse Outcomes Among Patients With Ischemic Stroke: A Prospective Cohort Study", "type": "source", "url": "https://doi.org/10.1161/JAHA.124.035837", "year": 2024}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3389/fnagi.2022.924984", "effect": "not extracted", "endpoint": "not extracted", "id": "source_17", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Non-linear association between serum spermidine and mild cognitive impairment: Results from a cross-sectional and longitudinal study", "type": "source", "url": "https://doi.org/10.3389/fnagi.2022.924984", "year": 2022}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1016/j.bbrep.2024.101642", "effect": "not extracted", "endpoint": "not extracted", "id": "source_18", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "5-ALA localises to the autophagy compartment and increases its fluorescence upon autophagy enhancement through caloric restriction and spermidine treatment in human glioblastoma", "type": "source", "url": "https://doi.org/10.1016/j.bbrep.2024.101642", "year": 2024}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3390/pathogens15040432", "effect": "not extracted", "endpoint": "not extracted", "id": "source_19", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Functional and Biochemical Characterization of Spermidine Synthase CauSpe3 from Candidozyma auris", "type": "source", "url": "https://doi.org/10.3390/pathogens15040432", "year": 2026}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1161/jaha.124.037465", "effect": "not extracted", "endpoint": "not extracted", "id": "source_20", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "High Plasma Polyamine Levels Are Associated With an Increased Risk of Poststroke Cognitive Impairment: A Multicenter Prospective Study From CATIS.", "type": "source", "url": "https://doi.org/10.1161/jaha.124.037465", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3390/ijms27073261", "effect": "not extracted", "endpoint": "not extracted", "id": "source_21", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Targeting Polyamine Metabolism in Colorectal Cancer: Apigenin Dismantles the HIF-1α/SMOX Positive Feedback Loop to Suppress Tumor Progression", "type": "source", "url": "https://doi.org/10.3390/ijms27073261", "year": 2026}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1080/10715762.2026.2625094", "effect": "not extracted", "endpoint": "not extracted", "id": "source_22", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Spermidine improve high copper diet-induced intestinal oxidative stress and microbiota community composition.", "type": "source", "url": "https://doi.org/10.1080/10715762.2026.2625094", "year": 2026}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1016/j.clnu.2026.106651", "effect": "not extracted", "endpoint": "not extracted", "id": "source_23", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Spermidine and spermine in elderly patients with coronary artery disease: a cross-sectional study of dietary intake and plasma and skeletal muscle concentrations.", "type": "source", "url": "https://doi.org/10.1016/j.clnu.2026.106651", "year": 2026}, {"comparator": "not extracted", "directness": "review-level", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_24", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Effects of Spermidine-Rich Rice Germ Extract Supplement on Biomarkers of Healthy Aging and Autophagy-Proof-of-Concept Pilot Study.", "type": "source", "url": "https://pubmed.ncbi.nlm.nih.gov/40862848/", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1186/s13578-021-00614-4", "effect": "not extracted", "endpoint": "not extracted", "id": "source_25", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "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", "type": "source", "url": "https://doi.org/10.1186/s13578-021-00614-4", "year": 2021}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1007/s00784-024-05924-8", "effect": "not extracted", "endpoint": "not extracted", "id": "source_26", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Treatment of peri-implant mucositis using spermidine and calcium chloride as local adjunctive delivery to non-surgical 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"risk_of_bias": "not appraised in public sidecar", "study": "Loss-of-function variant in spermidine/spermine N1-acetyl transferase like 1 ( SATL1 ) gene as an underlying cause of autism spectrum disorder", "type": "source", "url": "https://doi.org/10.1038/s41598-024-56253-5", "year": 2024}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1016/j.nutres.2024.10.006", "effect": "not extracted", "endpoint": "not extracted", "id": "source_31", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "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.", "type": "source", "url": "https://doi.org/10.1016/j.nutres.2024.10.006", "year": 2024}, {"comparator": "not extracted", "directness": "review-level", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_32", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "SPERMIDINE TOXICITY IN MITOCHONDRIAL DNA-DEFICIENT SACCHAROMYCES CEREVISIAE", "type": "source", "url": null, "year": 2022}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.22067/jhs.2022.74334.1118", "effect": "not extracted", "endpoint": "not extracted", "id": "source_33", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "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’", "type": "source", "url": "https://doi.org/10.22067/jhs.2022.74334.1118", "year": 2023}, {"comparator": "not extracted", "directness": "review-level", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_34", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Improving Vaccination in Older Adults by Inducing Autophagy With Spermidine", "type": "source", "url": null, "year": 2023}, {"comparator": "not extracted", "directness": "review-level", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_35", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Metabolic Responses to Spermidine Supplementation.", "type": "source", "url": null, "year": 2023}, {"comparator": "not extracted", "directness": "primary", "doi": "10.18632/aging.101354", "effect": "not extracted", "endpoint": "not extracted", "id": "source_36", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline", "type": "source", "url": "https://doi.org/10.18632/aging.101354", "year": 2018}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1186/s13195-019-0484-1", "effect": "not extracted", "endpoint": "not extracted", "id": "source_37", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)—study protocol for a randomized controlled trial", "type": "source", "url": "https://doi.org/10.1186/s13195-019-0484-1", "year": 2019}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1038/s12276-018-0149-3", "effect": "not extracted", "endpoint": "not extracted", "id": "source_38", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Spermidine restores dysregulated autophagy and polyamine synthesis in aged and osteoarthritic chondrocytes via EP300", "type": "source", "url": "https://doi.org/10.1038/s12276-018-0149-3", "year": 2018}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3389/fnut.2019.00108", "effect": "not extracted", "endpoint": "not extracted", "id": "source_39", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Polyamines in Food", "type": "source", "url": "https://doi.org/10.3389/fnut.2019.00108", "year": 2019}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1016/j.cortex.2018.09.014", "effect": "not extracted", "endpoint": "not extracted", "id": "source_40", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "The effect of spermidine on memory performance in older adults at risk for dementia: A randomized controlled trial.", "type": "source", "url": "https://doi.org/10.1016/j.cortex.2018.09.014", "year": 2018}, {"comparator": "not extracted", "directness": "review-level", "doi": "10.1016/j.foodres.2017.06.005", "effect": "not extracted", "endpoint": "not extracted", "id": "source_41", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "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.", "type": "source", "url": "https://doi.org/10.1016/j.foodres.2017.06.005", "year": 2017}, {"comparator": "not extracted", "directness": "review-level", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_42", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Autophagy-Enhancers to Reduce Sleep Disturbances", "type": "source", "url": null, "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_43", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "**Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.", "type": "source", "url": null, "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_44", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "**Directness** is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.", "type": "source", "url": null, "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_45", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "**Directional signal** is counted within the assigned outcome class only. A `no extracted directional signal` cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.", "type": "source", "url": null, "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_46", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "**Evidence tier** follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.", "type": "source", "url": null, "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_47", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Bruno 2025", "type": "source", "url": null, "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_48", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Autophagy-Enhancers to Reduce Sleep n.d.", "type": "source", "url": null, "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_49", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "SPERMIDINE TOXICITY in MITOCHONDRIAL 2022", "type": "source", "url": null, "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_50", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Improving Vaccination in Older 2023", "type": "source", "url": null, "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": null, "effect": "not extracted", "endpoint": "not extracted", "id": "source_51", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Metabolic Responses to Spermidine 2023", "type": "source", "url": null, "year": null}, {"comparator": "not extracted", "directness": "citation", "doi": "10.1371/journal.pmed.0020124", "effect": "not extracted", "endpoint": "not extracted", "id": "source_52", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Ioannidis 2005", "type": "source", "url": "https://doi.org/10.1371/journal.pmed.0020124", "year": null}], "publication_id": "0326ee6c-57b7-4644-a7c4-9c81b0c5541c", "screening": {"excluded": 0, "exclusion_reasons": ["No PRISMA full-text exclusion-stage filter was applied."], "flow": ["identified", "screened", "excluded_with_reasons", "included"], "identified": 42, "included": 42, "included_or_retained": 42, "screened": 42, "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."}}
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