source · application/json
source_3e14e9692f064303
sha256 e820e12d1a2d4b9ece7e51ee1918628774fd2166c822ab9c99ef5f6e433ec916
by researka:v2 · 2026-06-04 13:50:41.031689+04:00
{"publication_id": "8306a2c0-a1a4-4556-9e12-fce4eca92589", "traces": [{"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "Evidence-honesty note: 34/39 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. 38/39 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": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "This synthesis tests the thesis that evidence for Sirtuin Effects is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation.", "claim_id": "claim_2"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "To address this question, we conducted an AI-assisted structured evidence synthesis with an auditable retrieval and appraisal trail, prioritizing direct interventional hard-endpoint evidence over mechanistic or preclinical findings.", "claim_id": "claim_3"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "Preclinical models support a plausible anti-inflammatory role, as NAD+ supplementation improved endothelial function in a SIRT3-dependent manner (Cao 2022), but fenofibrate's anti-inflammatory effect in obese patients was mediated via the SIRT1/fetuin-A axis (Noureldein 2015; P < 0.001).", "claim_id": "claim_4"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "The evidence therefore reveals a pronounced context-dependency: context-specific sirtuin-modulation signals emerge most clearly within pharmacological co-interventions in diabetes or dietary supplementation trials, whereas standalone sirtuin-activator interventions show predominantly null or inconsistent effects.", "claim_id": "claim_5"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "Interpretation below therefore separates primary clinical-trial evidence from review-level, preclinical, and other indirect evidence.", "claim_id": "claim_6"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "This manuscript is reported as a 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-sirtuin_effects-v06-DAILY-2026-06-04T09-46-12Z-R2`.", "claim_id": "claim_7"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text.", "claim_id": "claim_8"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`.", "claim_id": "claim_9"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, dosing and pharmacokinetics, immune, immune and inflammation, longevity, muscle function); 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_10"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "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_11"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "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_12"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |", "claim_id": "claim_13"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "| Contextual Adjacent Evidence | n=20; claims=649 | no extracted directional signal in 19/20 sources | 1 direct; 15 indirect; 2 mechanistic; 2 review | limited corpus depth in this outcome class |", "claim_id": "claim_14"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "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_15"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "20 included sources were assigned to this outcome class. Directional coding: null=19, positive=1. Directness coding: direct=1, indirect=15, mechanistic=2, review=2.", "claim_id": "claim_16"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "6 included sources were assigned to this outcome class. Directional coding: null=4, unclear=2. Directness coding: indirect=5, review=1.", "claim_id": "claim_17"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "4 included sources were assigned to this outcome class. Directional coding: null=4. Directness coding: indirect=2, review=2.", "claim_id": "claim_18"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=2, mechanistic=1.", "claim_id": "claim_19"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=2.", "claim_id": "claim_20"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "2 included sources were assigned to this outcome class. Directional coding: negative=1, null=1. Directness coding: mechanistic=1, review=1.", "claim_id": "claim_21"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.", "claim_id": "claim_22"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "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_23"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "Several conclusions in the synthesis rest on a single study whose finding cannot be replicated within the corpus. When a conclusion depends on a single unreplicated trial, the confidence interval around its true effect is effectively infinite, and any cross-domain synthesis built on that signal carries an elevated risk of overfitting to one dataset.", "claim_id": "claim_24"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "No study in the corpus measured patient-centered functional endpoints such as gait speed, grip strength, fall incidence, or activities-of-daily-living disability — outcomes that anchor geriatric anti-aging frameworks (Cruz-Jentoft 2019). The literature is dominated by gene-expression and protein-level surrogates: SIRT1 mRNA, SIRT3 activity, NF-κB phosphorylation, and similar molecular readouts. While mechanistically informative, these surrogates carry the risk flagged by Ioannidis 2005 that biomarker associations do not guarantee hard-outcome validity. Additionally, dose–response relationships for sirtuin-activating compounds remain poorly characterized — the resveratrol dose tested by Garcia-Martinez 2023 (1000 mg/day) was not compared against lower or higher doses in the same population, and the cinnamon dose in Davari 2020 yielded non-significant SIRT1 effects (P = 0.29) without a dose-escalation arm. Until functional and hard clinical endpoints are measured alongside sirtuin-expression changes, the translational significance of the observed molecular signals remains indeterminate.", "claim_id": "claim_25"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "For sirtuin effects, the final interpretation is deliberately tiered: the retained clinical and mechanistic evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation.The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.", "claim_id": "claim_26"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "This synthesis maps 39 included sources on Sirtuin Effects across 8 outcome classes and 218 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.", "claim_id": "claim_27"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "Across 39 curated reference papers, the evidence base for Sirtuin Effects shows a context-dependent profile. Positive signals appear in: contextual other. Negative signals appear in: immune. Null findings dominate: contextual other, cardiometabolic. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Sirtuin Effects anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.", "claim_id": "claim_28"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "Additional corpus sources included animal/preclinical evidence; the strongest unresolved contrast is the mechanism vs clinical between Werida 2023 and Liu 2021 on contextual adjacent evidence (severity 4/5), which defines the boundary condition future studies must test rather than smooth over.", "claim_id": "claim_29"}, {"candidate_sources": [{"doi": "10.1186/s12933-025-03013-y", "study": "Nowak-Szwed 2025", "url": "https://doi.org/10.1186/s12933-025-03013-y"}, {"doi": "10.3390/ijms24087422", "study": "Garcia-Martinez 2023", "url": "https://doi.org/10.3390/ijms24087422"}, {"doi": "10.1038/s41392-022-01257-8", "study": "Wu 2022", "url": "https://doi.org/10.1038/s41392-022-01257-8"}, {"doi": "10.1186/s12902-023-01511-2", "study": "Werida 2023", "url": "https://doi.org/10.1186/s12902-023-01511-2"}, {"doi": "10.1038/s41387-021-00168-x", "study": "Nikooyeh 2021", "url": "https://doi.org/10.1038/s41387-021-00168-x"}], "claim": "Prior reviews in the corpus (Noureldein 2015) emphasize convergent signals on Sirtuin Effects. This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.", "claim_id": "claim_30"}]}
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