source · application/json
source_bc572d2e263449b5
sha256 6bac4f2d47dcf7a9bc9689f4bd5c220f3fe5ce953f025505a73d8abbcd59d786
by researka:v2 · 2026-06-24 03:26:22.890024+04:00
{"publication_id": "0326ee6c-57b7-4644-a7c4-9c81b0c5541c", "traces": [{"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "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.", "claim_id": "claim_1"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "claim": "This paper synthesizes evidence on Spermidine supplementation across 42 included source papers and 1250 high-confidence extracted claims.", "claim_id": "claim_2"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "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.", "claim_id": "claim_3"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "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.", "claim_id": "claim_4"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "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.", "claim_id": "claim_5"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "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`.", "claim_id": "claim_6"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "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.", "claim_id": "claim_7"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "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.", "claim_id": "claim_8"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "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.", "claim_id": "claim_9"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "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.", "claim_id": "claim_10"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "claim": "| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |", "claim_id": "claim_11"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "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 |", "claim_id": "claim_12"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "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.", "claim_id": "claim_13"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "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.", "claim_id": "claim_14"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "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.", "claim_id": "claim_15"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "claim": "3 included sources were assigned to this outcome class. Directional coding: null=1, positive=2. Directness coding: direct=1, indirect=2.", "claim_id": "claim_16"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "claim": "3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: mechanistic=3.", "claim_id": "claim_17"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "claim": "2 included sources were assigned to this outcome class. Directional coding: null=2. 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Directional coding: null=1. Directness coding: review=1.", "claim_id": "claim_23"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "claim": "1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: direct=1.", "claim_id": "claim_24"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "claim": "Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.", "claim_id": "claim_25"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "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.", "claim_id": "claim_26"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "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.", "claim_id": "claim_27"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "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.", "claim_id": "claim_28"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "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.", "claim_id": "claim_29"}, {"candidate_sources": [{"doi": "10.3390/cells10010095", "study": "Spermidine and Rapamycin Reveal Distinct Autophagy Flux Response and Cargo Receptor Clearance Profile", "url": "https://doi.org/10.3390/cells10010095"}, {"doi": "10.1007/s12035-026-05763-6", "study": "Spermidine Attenuates Neuroimmune Dysfunction in Gulf War Illness via Modulation of the Gut- Brain Axis", "url": "https://doi.org/10.1007/s12035-026-05763-6"}, {"doi": "10.3390/biomedicines11051403", "study": "Whole Blood Spermine/Spermidine Ratio as a New Indicator of Sarcopenia Status in Older Adults", "url": "https://doi.org/10.3390/biomedicines11051403"}, {"doi": "10.3390/nu15081852", "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", "url": "https://doi.org/10.3390/nu15081852"}, {"doi": "10.1111/acel.70545", "study": "Spermidine Mitigates Immune Cell Senescence and Boosts Vaccine Responses in Healthy Older Adults—A Pilot Study", "url": "https://doi.org/10.1111/acel.70545"}], "claim": "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.", "claim_id": "claim_30"}]}
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