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Additional corpus sources included animal/preclinical evidence; mechanistic work is consistent with sirtuins as conserved NAD+-dependent deacetylases linking metabolism to longevity, but clinical translation remains heterogeneous across cardiometabolic, immune, muscle-function, and contextual outcomes (Wu 2022; Krekora 2026). We conducted an AI-assisted structured evidence synthesis with a fully auditable source-level trail, screening 41 curated references and characterizing each by design, directness, and effect direction across non-orthogonal outcome domains. Cardiometabolic associations were largely null or exploratory: empagliflozin altered SIRT6 (P < 0.001) and SIRT4 (P = 0.018) after myocardial infarction in Nowak-Szwed 2025, but no prospective cohort has yet linked baseline SIRT1 to hard cardiovascular endpoints (Biscetti 2024). Immune and inflammatory sirtuin readouts were generally unfavorable in synthesis, with fenofibrate reviews reporting SIRT1 increases but only as a mechanistic correlate of inflammation reduction (Noureldein 2015; P < 0.001). The 41-reference set surfaces cross-study disagreements, most prominently indirectness gaps between direct human RCTs and indirect observational or mechanistic data on the same contextual outcome class. Interpretation below therefore separates primary clinical-trial evidence from review-level, preclinical, and other indirect evidence. ## Abstract Evidence-honesty note: 36/41 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. 38/41 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes evidence on sirtuin intervention aging effects across 41 included source papers and 1394 high-confidence extracted claims. The evidence profile contains 3 direct clinical sources, 37 adjacent clinical sources, and 1 mechanistic or model-system source, with 116 cross-study disagreements across the evidence base. Positive study-level signals are not the dominant direction in any outcome class; null signals are summarized in the contextual adjacent evidence, cardiometabolic, deficiency prevalence, dosing and pharmacokinetics, immune and inflammation, and longevity outcome classes; negative signals are summarized in the immune and inflammation outcome class; mixed or heterogeneous signals are summarized in the muscle function outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that sirtuin intervention aging effects should be treated as a bounded geroscience hypothesis: the retained clinical and mechanistic evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim. ## Results | Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation | |---|---|---|---|---| | Contextual Adjacent Evidence | n=22; claims=779 | no extracted directional signal in 21/22 sources | 2 direct; 18 indirect; 1 protocol; 1 review | limited corpus depth in this outcome class | | Cardiometabolic | n=9; claims=377 | no extracted directional signal in 7/9 sources | 1 direct; 8 indirect | limited corpus depth in this outcome class | | Deficiency Prevalence | n=4; claims=114 | no extracted directional signal in 4/4 sources | 4 indirect | limited corpus depth in this outcome class | | Immune and Inflammation | n=2; claims=52 | no extracted directional signal in 1/2 sources | 1 indirect; 1 review | limited corpus depth in this outcome class | | Muscle Function | n=2; claims=49 | no extracted directional signal in 1/2 sources | 2 indirect | limited corpus depth in this outcome class | | Dosing and Pharmacokinetics | n=1; claims=22 | no extracted directional signal in 1/1 sources | 1 review | single-source slice; hypothesis-generating | | Longevity | n=1; claims=1 | no extracted directional signal in 1/1 sources | 1 mechanistic | single-source slice; hypothesis-generating | **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. This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate. ### Contextual Adjacent Evidence Outcomes 22 included sources were assigned to this outcome class. Directional coding: null=21, positive=1. Directness coding: direct=2, indirect=18, protocol=1, review=1. ### Cardiometabolic Outcomes 9 included sources were assigned to this outcome class. Directional coding: null=7, unclear=2. Directness coding: direct=1, indirect=8. ### Deficiency Prevalence Outcomes 4 included sources were assigned to this outcome class. Directional coding: null=4. Directness coding: indirect=4. ### Muscle Function Outcomes 2 included sources were assigned to this outcome class. Directional coding: negative=1, null=1. Directness coding: indirect=2. ### Dosing Pharmacokinetics Outcomes 1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: review=1. ### Immune Outcomes 1 included source were assigned to this outcome class. Directional coding: negative=1. Directness coding: review=1. 1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1. Evidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim. ### Longevity Outcomes 1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: mechanistic=1. ## Limitations **Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim. A second structural limitation is single-trial generalization risk on outcomes that appear in only one or two sources and therefore cannot be replicated within the corpus itself. Several non-trivial findings stand on a single study: Shi 2025 reports a negative effect of irisin-mediated SIRT1 modulation on glucocorticoid-induced sarcopenia in n = 6 per-group animal arms, and that result is not mirrored by a comparable human RCT in the corpus. When effect-direction disagreements appear within a single outcome class — for example the null vs positive tension between Werida 2023 and Bo 2018 on contextual other, or the null vs negative tension between Cho 2022 and Shi 2025 on muscle function — the resolution has to be carried by the evidence synthesis per-domain RoB assessment rather than by an independent within-corpus replication, and that is a ceiling on confidence that the limitations section is obliged to flag explicitly rather than paper over. Population specificity is a third limitation that the curated corpus makes unusually visible. Adjacent disease-specific cohorts — Bielach-Bazyluk 2025 (chronic kidney disease including peritoneal dialysis), Monge 2025 (burn trauma with murine comparator arms), Rum 2025 (type A dissection vs ascending aneurysm tissue), Tsai 2021 (pancreatic adenocarcinoma with KLF10 deficiency), and Liu 2014 (colon cancer) — further narrow the demographic envelope. External validity to a non-diabetic, non-oncologic, non-critically-ill older population is therefore a stated boundary of the synthesis, not an extrapolable claim. The fifth limitation is the mechanism-to-clinic gap. The most explicit mechanistic claims in the corpus — Krekora 2026 framing SIRT1 as a molecular link between cellular senescence and heart failure, Budziak 2025 reviewing SIRT1 as a therapeutic target in pulmonary arterial hypertension, Sugishita 2024 positioning sirtuins as biomarkers of healthy life expectancy, and the Wu 2022 review noting that an extra copy of Sir2 extended yeast lifespan by about 40% — are preclinical, narrative, or model-organism, and the human-RCT layer that would normally bridge them is exactly the layer missing here. The synthesis can therefore document the mechanistic plausibility chain end-to-end, but it cannot certify that any of these mechanistic links is sufficient, in the populations actually studied, to move a hard aging endpoint — and that uncertainty is a feature of the evidence base, not an artifact of the synthesis. ## Conclusion For sirtuin intervention aging 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. ## What This Synthesis Adds This synthesis maps 41 included sources on Sirtuin Intervention Aging Effects across 8 outcome classes and 116 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. Across 41 curated reference papers, the evidence base for Sirtuin shows a context-dependent profile. Positive signals appear in: contextual other. Negative signals appear in: muscle function, immune. Null findings dominate: contextual other, cardiometabolic. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Sirtuin 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. The strongest unresolved contrast is the null vs positive between Werida 2023 and Bo 2018 on contextual adjacent evidence (severity 4/5), which defines the boundary condition future studies must test rather than smooth over. Prior reviews in the corpus (Noureldein 2015) emphasize convergent signals on Sirtuin Intervention Aging 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. ### Boundary-Condition Matrix | Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary | |---|---:|---:|---|---| | longevity | 0 | 1 | null | direct interventional hard-endpoint gap | | muscle function | 0 | 2 | negative, null | conflict-resolution gap | | immune and inflammation | 0 | 1 | negative | direct interventional hard-endpoint gap | | cardiometabolic | 1 | 8 | null, unclear | replication gap | | deficiency prevalence | 0 | 4 | null | direct interventional hard-endpoint gap | | dosing and pharmacokinetics | 0 | 1 | null | direct interventional hard-endpoint gap | | immune and inflammation | 0 | 1 | null | direct interventional hard-endpoint gap | | contextual adjacent evidence | 2 | 20 | null, positive | conflict-resolution gap | ### Evidence-Gap Priority | Priority | Gap | Rationale | |---|---|---| | P1 | longevity: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: null | | P2 | muscle function: conflict-resolution gap | 0 direct and 2 indirect sources; direction profile: negative, null | | P3 | immune and inflammation: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: negative | | P4 | cardiometabolic: replication gap | 1 direct and 8 indirect sources; direction profile: null, unclear | | P5 | deficiency prevalence: direct interventional hard-endpoint gap | 0 direct and 4 indirect sources; direction profile: null | ### Next-Study Design Recommendation The next high-yield study for Sirtuin Intervention Aging Effects should target the **longevity** evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 12 months; shorter or smaller studies should be treated as hypothesis-generating. ## Evidence Snapshot The manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement. ### Load-Bearing Included Studies - Additional corpus sources included animal/preclinical evidence; Werida 2023; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=positive; representative statistic=P < 0.001. - Daneshi-Maskooni 2017; tier=A1; directness=direct; endpoint=cardiometabolic; direction=null. - Bo 2018; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=null. - Noureldein 2015; tier=B1; directness=review; endpoint=immune; direction=negative; representative statistic=P < 0.001. - Nowak-Szwed 2025; tier=B2; directness=indirect; endpoint=cardiometabolic; direction=unclear; representative statistic=P < 0.001. - Garcia-Martinez 2023; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null. - Wu 2022; tier=B2; directness=indirect; endpoint=cardiometabolic; direction=unclear. - Zhang 2025; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null. - Nguyen 2026; tier=B2; directness=indirect; endpoint=deficiency prevalence; direction=null; representative statistic=P = 0.058. - Nikooyeh 2021; tier=B2; directness=indirect; endpoint=cardiometabolic; direction=null. ### Source Classification Map Each retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement. - Effect of coadministration of omega-3 fatty acids with glimepiride on glycemic control, lipid profile, irisin, and sirtuin-1 in type 2 diabetes mellitus patients: a randomized controlled trial: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=positive; claims=80. - The effects of green cardamom on blood glucose indices, lipids, inflammatory factors, paraxonase-1, sirtuin-1, and irisin in patients with nonalcoholic fatty liver disease and obesity: study protocol for a randomized controlled trial: outcome=cardiometabolic; directness=direct; tier=A1; direction=null; claims=28. - Impact of sirtuin-1 expression on H3K56 acetylation and oxidative stress: a double-blind randomized controlled trial with resveratrol supplementation: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=null; claims=16. - Fenofibrate reduces inflammation in obese patients with or without type 2 diabetes mellitus via sirtuin 1/fetuin A axis.: outcome=immune; directness=review; tier=B1; direction=negative; claims=1. - Sirtuins and regulatory miRNAs as epigenetic determinants of empagliflozin-mediated recovery after acute myocardial infarction: outcome=cardiometabolic; directness=indirect; tier=B2; direction=unclear; claims=124. - Effect of Resveratrol on Markers of Oxidative Stress and Sirtuin 1 in Elderly Adults with Type 2 Diabetes: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=106. - The sirtuin family in health and disease: outcome=cardiometabolic; directness=indirect; tier=B2; direction=unclear; claims=106. - Epigallocatechin-3-Gallate from Green Tea Reduces Vascular Aging and Endothelial Cell Senescence by Modifying Autophagy and Ferroptosis through the Sirtuin 1 Signaling Pathway: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=82. - Endothelial Sirtuins and Mitochondrial Function Are Associated With Testosterone Status: Implications for Accelerated Vascular Aging in Middle‐Age and Older Men With Low Testosterone: outcome=deficiency prevalence; directness=indirect; tier=B2; direction=null; claims=65. - The effect of daily intake of vitamin D-fortified yogurt drink, with and without added calcium, on serum adiponectin and sirtuins 1 and 6 in adult subjects with type 2 diabetes: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=62. - Sirtuin Expression in Age-Associated Hepatic Response to Burn Trauma: Translational and Clinical Insights From a Murine Model: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=56. - Impact of Dietary Modifications on Plasma Sirtuins 1, 3 and 5 in Older Overweight Individuals Undergoing 12-Weeks of Circuit Training: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=53. - Effects of cinnamon supplementation on expression of systemic inflammation factors, NF-kB and Sirtuin-1 (SIRT1) in type 2 diabetes: a randomized, double blind, and controlled clinical trial: outcome=immune inflammation; directness=indirect; tier=B2; direction=null; claims=51. - Changes in the Systemic Expression of Sirtuin-1 and Oxidative Stress after Intravitreal Anti-Vascular Endothelial Growth Factor in Patients with Retinal Vein Occlusion: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=40. - Taurine, Sirtuin-1 and TNF- α levels in different aged adults with periodontitis: a pilot study: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=39. - Impact of Exercise Intensity on Systemic Oxidative Stress, Inflammatory Responses, and Sirtuin Levels in Healthy Male Volunteers: outcome=muscle function; directness=indirect; tier=B2; direction=null; claims=38. - Sechium edule var. nigrum spinosum (Chayote) Increases the mRNA Expression of Genes Encoding Sirtuins in Older Adults with Type 2 Diabetes Mellitus: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=38. - The Sirtuin 3 Expression Profile Is Associated with Pathological and Clinical Outcomes in Colon Cancer Patients: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=38. - The Prognostic and Clinicopathological Roles of Sirtuin-3 in Various Cancers: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=37. - Gene Expression of Sirtuin-1 and Endogenous Secretory Receptor for Advanced Glycation End Products in Healthy and Slightly Overweight Subjects after Caloric Restriction and Resveratrol Administration: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=36. - Effects of Citicoline-Based Supplementation on Lipid Peroxidation Markers and Sirtuin-1 Expression in Ischemic Stroke: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=31. - The Relationship Between Aortic Tissue Sirtuin 1 Levels and Type A Aortic Dissections and Ascending Aortic Aneurysms: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=29. - Granulosa-Lutein Cell Sirtuin Gene Expression Profiles Differ between Normal Donors and Infertile Women: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=26. - Deciphering the Role of Sirtuin‐1 Gene Polymorphism in Diabetic Nephropathy: A Systematic Review and Meta‐Analysis: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=25. - Association Between Salivary Sirtuin-1 Levels and Periodontitis: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=24. - Phase 1, Single‐Center, Double‐Blind, Randomized, Placebo‐Controlled Studies of the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Oral Doses of the Sirtuin 6 Activator SP‐624 in Healthy Adults: outcome=dosing pharmacokinetics; directness=review; tier=B2; direction=null; claims=22. - Serum and follicular fluid levels of sirtuin 1, sirtuin 6, and resveratrol in women undergoing in vitro fertilization: an observational, clinical study: outcome=deficiency prevalence; directness=indirect; tier=B2; direction=null; claims=20. - Evaluation of Sirtuin 1 (SIRT1) and Sirtuin 3 (SIRT3) in serum and cerebrospinal fluid following fatal traumatic brain injury: outcome=deficiency prevalence; directness=indirect; tier=B2; direction=null; claims=18. - Five Days Periodic Fasting Elevates Levels of Longevity Related Christensenella and Sirtuin Expression in Humans: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=17. - Elevated Sirtuin 1 Levels in Patients with Chronic Kidney Disease, Including on Peritoneal Dialysis: Associations with Cardiovascular Risk and Peritoneal Fibrosis: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=13. - The effect of obesity and aging on NAD + /Sirtuin metabolism transcription and DNA methylation in subcutaneous adipose tissue of monozygotic twin pairs discordant for BMI: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=12. - Irisin Increases Sirtuin 1 to Improve Glucocorticoid-Induced Sarcopenia and Mitochondrial Dysfunction: outcome=muscle function; directness=indirect; tier=B2; direction=negative; claims=11. - Upregulating sirtuin 6 ameliorates glycolysis, EMT and distant metastasis of pancreatic adenocarcinoma with krüppel-like factor 10 deficiency: outcome=deficiency prevalence; directness=indirect; tier=B2; direction=null; claims=11. - Single Nucleotide Polymorphisms of the Sirtuin 1 (SIRT1) Gene are Associated With age-Related Macular Degeneration in Chinese Han Individuals: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=7. - Statin suppresses sirtuin 6 through miR-495, increasing FoxO1-dependent hepatic gluconeogenesis: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=7. - Effects of perinatal factors on sirtuin 3, 8-hydroxy-2′- deoxyguanosine, brain-derived neurotrophic factor and serotonin in cord blood and early breast milk: an observational study: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=4. - Can Sirtuin 1 Serve as a Therapeutic Target in Pulmonary Arterial Hypertension? A Comprehensive Review: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=2. - Evaluation of sirtuin 1 as a predictor of cardiovascular outcomes in diabetic patients with limb-threatening ischemia: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=1. - Nicotinamide Adenine Dinucleotide (NAD)-Dependent Protein Deacetylase, Sirtuin, as a Biomarker of Healthy Life Expectancy: A Mini-Review: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=1. - Sirtuin 1 is a key molecular link between cellular senescence and heart failure: outcome=longevity; directness=mechanistic; tier=C1; direction=null; claims=1. ### Classification Criteria - **Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices. - **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. - **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. - **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. ### Load-Bearing Tensions - Additional corpus sources included animal/preclinical evidence; severity 4 null vs negative: Shi 2025 vs Cho 2022; Shi 2025 (negative on muscle function) vs Cho 2022 (null on muscle function) — partial conflict - Severity 4 null vs positive: Werida 2023 vs Bo 2018; Werida 2023 (positive on contextual other) vs Bo 2018 (null on contextual other) — partial conflict - Severity 3 indirectness gap: Garcia-Martinez 2023 vs Werida 2023; Werida 2023 (direct, A1) vs Garcia-Martinez 2023 (indirect) on contextual other — direct vs indirect must be kept separate - Severity 3 indirectness gap: Garcia-Martinez 2023 vs Bo 2018; Bo 2018 (direct, A1) vs Garcia-Martinez 2023 (indirect) on contextual other — direct vs indirect must be kept separate - Severity 3 indirectness gap: Werida 2023 vs Monge 2025; Werida 2023 (direct, A1) vs Monge 2025 (indirect) on contextual other — direct vs indirect must be kept separate - Severity 3 indirectness gap: Werida 2023 vs Sayedyousef 2025; Werida 2023 (direct, A1) vs Sayedyousef 2025 (indirect) on contextual other — direct vs indirect must be kept separate - Severity 3 indirectness gap: Werida 2023 vs Sugishita 2024; Werida 2023 (direct, A1) vs Sugishita 2024 (indirect) on contextual other — direct vs indirect must be kept separate - Severity 3 indirectness gap: Werida 2023 vs Zhang 2025; Werida 2023 (direct, A1) vs Zhang 2025 (indirect) on contextual other — direct vs indirect must be kept separate ## Methods ### Review type and protocol 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-sirtuin_intervention_aging_effects-v06-DAILY-2026-06-21T20-04-33Z`. ### Information sources Sources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-21. ### Search strategy The following topic-anchored queries were executed against the information sources listed above: - `sirtuin intervention aging effects aging` - `sirtuin intervention aging effects older adults` - `sirtuin intervention aging effects randomized controlled trial` - `sirtuin aging` - `sirtuin older adults` - `sirtuin randomized controlled trial` - `intervention aging aging` - `intervention aging older adults` - `intervention aging randomized controlled trial` ### Eligibility criteria - Sources whose primary content addresses sirtuin intervention aging effects. - Sources with extractable quantitative or qualitative findings. - Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable. - Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle). ### Selection of sources of evidence The synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 189 records in the receipt-candidate union, 69 were classified as source candidates and 41 were admitted as traceable synthesis sources. Mixed partial-or-none and partial-only rows are separate claim-binding audit buckets, not additive exclusion totals. No additional records were excluded after final source admission. ### source admission funnel | Admission bucket | n | |---|---:| | Receipt candidate union | 189 | | Classified source candidates | 69 | | No extractable claims | 40 | | None-only claim binding | 9 | | Mixed partial-or-none claim-binding candidates | 55 | | Partial-only claim-binding candidates | 10 | | Strict high-confidence sources | 6 | | Admitted final sources | 41 | ### Exclusion reasons - No records were excluded at the gates instrumented for this run: the eligibility criteria above were applied during retrieval and claim-binding but produced no post-screening exclusions with recorded counts for this corpus. ### Data items 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. ### Risk-of-bias appraisal 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. ### Synthesis approach Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, dosing and pharmacokinetics, immune and inflammation, 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. ### AI-use disclosure 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. ### Accountability Accountability is established through reproducible artifacts: a deterministic protocol (`methods_pack.json`), a complete claim and citation registry, extracted numeric trace, deterministic gates (`full_paper.journal_surface.json`, `pre_submit_gate.json`, `artifact_consistency.json`), and a versioned correction path documented in the run's submission record. Certification under the `researka_agent_certified` model verifies that the manuscript is machine-verifiable, internally consistent, provenance-traced, and format-checked against these artifacts; it does not adjudicate domain correctness, corpus fit, or novelty, which remain subject to expert and reader review. Additional corpus sources included animal/preclinical evidence; additional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Wasserfurth 2021, Davari 2020, Hwang 2020, Gavia-Garcia 2026, Yu 2016, Roggerio 2018, Sokrateva 2026, Gonzalez-Fernandez 2019, Moin 2026, Lorente 2026, Rigdon 2024, Bodis 2019, Poniatowski 2026, Lilja 2021, Aghasi 2018, Lapatto 2026, Chen 2015, Shi 2020, Nyarady 2020. ## References - **Nowak-Szwed 2025.** _Sirtuins and regulatory miRNAs as epigenetic determinants of empagliflozin-mediated recovery after acute myocardial infarction._ Cardiovascular Diabetology, 2025. DOI: 10.1186/s12933-025-03013-y. PMID: 41462250. - **Garcia-Martinez 2023.** _Effect of Resveratrol on Markers of Oxidative Stress and Sirtuin 1 in Elderly Adults with Type 2 Diabetes._ International Journal of Molecular Sciences, 2023. DOI: 10.3390/ijms24087422. PMID: 37108584. - **Wu 2022.** _The sirtuin family in health and disease._ Signal Transduction and Targeted Therapy, 2022. DOI: 10.1038/s41392-022-01257-8. PMID: 36581622. - **Zhang 2025.** _Epigallocatechin-3-Gallate from Green Tea Reduces Vascular Aging and Endothelial Cell Senescence by Modifying Autophagy and Ferroptosis through the Sirtuin 1 Signaling Pathway._ ACS Omega, 2025. DOI: 10.1021/acsomega.5c03880. PMID: 40918353. - **Werida 2023.** _Effect of coadministration of omega-3 fatty acids with glimepiride on glycemic control, lipid profile, irisin, and sirtuin-1 in type 2 diabetes mellitus patients: a randomized controlled trial._ BMC Endocrine Disorders, 2023. DOI: 10.1186/s12902-023-01511-2. PMID: 38001474. - **Nguyen 2026.** _Endothelial Sirtuins and Mitochondrial Function Are Associated With Testosterone Status: Implications for Accelerated Vascular Aging in Middle‐Age and Older Men With Low Testosterone._ Aging Cell, 2026. DOI: 10.1111/acel.70457. PMID: 41986916. - **Nikooyeh 2021.** _The effect of daily intake of vitamin D-fortified yogurt drink, with and without added calcium, on serum adiponectin and sirtuins 1 and 6 in adult subjects with type 2 diabetes._ Nutrition & Diabetes, 2021. DOI: 10.1038/s41387-021-00168-x. PMID: 34389701. - **Monge 2025.** _Sirtuin Expression in Age-Associated Hepatic Response to Burn Trauma: Translational and Clinical Insights From a Murine Model._ Cureus, 2025. DOI: 10.7759/cureus.82663. PMID: 40400796. - **Wasserfurth 2021.** _Impact of Dietary Modifications on Plasma Sirtuins 1, 3 and 5 in Older Overweight Individuals Undergoing 12-Weeks of Circuit Training._ Nutrients, 2021. DOI: 10.3390/nu13113824. PMID: 34836079. - **Davari 2020.** _Effects of cinnamon supplementation on expression of systemic inflammation factors, NF-kB and Sirtuin-1 (SIRT1) in type 2 diabetes: a randomized, double blind, and controlled clinical trial._ Nutrition Journal, 2020. DOI: 10.1186/s12937-019-0518-3. PMID: 31901246. - **Hwang 2020.** _Changes in the Systemic Expression of Sirtuin-1 and Oxidative Stress after Intravitreal Anti-Vascular Endothelial Growth Factor in Patients with Retinal Vein Occlusion._ Biomolecules, 2020. DOI: 10.3390/biom10101414. PMID: 33036304. - **Sayedyousef 2025.** _Taurine, Sirtuin-1 and TNF-α levels in different aged adults with periodontitis: a pilot study._ BMC Oral Health, 2025. DOI: 10.1186/s12903-025-06690-z. PMID: 40847336. - **Gavia-Garcia 2026.** _Sechium edule var. nigrum spinosum (Chayote) Increases the mRNA Expression of Genes Encoding Sirtuins in Older Adults with Type 2 Diabetes Mellitus._ Molecules, 2026. DOI: 10.3390/molecules31071182. PMID: 41976223. - **Liu 2014.** _The Sirtuin 3 Expression Profile Is Associated with Pathological and Clinical Outcomes in Colon Cancer Patients._ BioMed Research International, 2014. DOI: 10.1155/2014/871263. PMID: 25105144. - **Cho 2022.** _Impact of Exercise Intensity on Systemic Oxidative Stress, Inflammatory Responses, and Sirtuin Levels in Healthy Male Volunteers._ International Journal of Environmental Research and Public Health, 2022. DOI: 10.3390/ijerph191811292. PMID: 36141561. - **Yu 2016.** _The Prognostic and Clinicopathological Roles of Sirtuin-3 in Various Cancers._ PLoS ONE, 2016. DOI: 10.1371/journal.pone.0159801. PMID: 27483432. - **Roggerio 2018.** _Gene Expression of Sirtuin-1 and Endogenous Secretory Receptor for Advanced Glycation End Products in Healthy and Slightly Overweight Subjects after Caloric Restriction and Resveratrol Administration._ Nutrients, 2018. DOI: 10.3390/nu10070937. PMID: 30037068. - **Sokrateva 2026.** _Effects of Citicoline-Based Supplementation on Lipid Peroxidation Markers and Sirtuin-1 Expression in Ischemic Stroke._ Current Issues in Molecular Biology, 2026. DOI: 10.3390/cimb48030314. PMID: 41899465. - **Rum 2025.** _The Relationship Between Aortic Tissue Sirtuin 1 Levels and Type A Aortic Dissections and Ascending Aortic Aneurysms._ Brazilian Journal of Cardiovascular Surgery, 2025. DOI: 10.21470/1678-9741-2024-0218. PMID: 41259217. - **Daneshi-Maskooni 2017.** _The effects of green cardamom on blood glucose indices, lipids, inflammatory factors, paraxonase-1, sirtuin-1, and irisin in patients with nonalcoholic fatty liver disease and obesity: study protocol for a randomized controlled trial._ Trials, 2017. DOI: 10.1186/s13063-017-1979-3. PMID: 28592311. - **Gonzalez-Fernandez 2019.** _Granulosa-Lutein Cell Sirtuin Gene Expression Profiles Differ between Normal Donors and Infertile Women._ International Journal of Molecular Sciences, 2019. DOI: 10.3390/ijms21010295. PMID: 31906251. - **Moin 2026.** _Deciphering the Role of Sirtuin‐1 Gene Polymorphism in Diabetic Nephropathy: A Systematic Review and Meta‐Analysis._ Journal of Diabetes Research, 2026. 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PMID: 30556451. - **Poniatowski 2026.** _Evaluation of Sirtuin 1 (SIRT1) and Sirtuin 3 (SIRT3) in serum and cerebrospinal fluid following fatal traumatic brain injury._ International Journal of Legal Medicine, 2026. DOI: 10.1007/s00414-025-03626-8. PMID: 41107542. - **Lilja 2021.** _Five Days Periodic Fasting Elevates Levels of Longevity Related Christensenella and Sirtuin Expression in Humans._ International Journal of Molecular Sciences, 2021. DOI: 10.3390/ijms22052331. PMID: 33652686. - **Aghasi 2018.** _The effects of green cardamom supplementation on blood glucose, lipids profile, oxidative stress, sirtuin-1 and irisin in type 2 diabetic patients: a study protocol for a randomized placebo-controlled clinical trial._ BMC Complementary and Alternative Medicine, 2018. DOI: 10.1186/s12906-017-2068-6. PMID: 29343256. - **Bo 2018.** _Impact of sirtuin-1 expression on H3K56 acetylation and oxidative stress: a double-blind randomized controlled trial with resveratrol supplementation._ Acta Diabetologica, 2018. DOI: 10.1007/s00592-017-1097-4. PMID: 29330620. - **Bielach-Bazyluk 2025.** _Elevated Sirtuin 1 Levels in Patients with Chronic Kidney Disease, Including on Peritoneal Dialysis: Associations with Cardiovascular Risk and Peritoneal Fibrosis._ International Journal of Molecular Sciences, 2025. DOI: 10.3390/ijms26189033. PMID: 41009597. - **Lapatto 2026.** _The effect of obesity and aging on NAD + /Sirtuin metabolism transcription and DNA methylation in subcutaneous adipose tissue of monozygotic twin pairs discordant for BMI._ International Journal of Obesity (2005), 2026. DOI: 10.1038/s41366-025-02007-w. PMID: 41491271. - **Shi 2025.** _Irisin Increases Sirtuin 1 to Improve Glucocorticoid-Induced Sarcopenia and Mitochondrial Dysfunction._ Cells, 2025. DOI: 10.3390/cells14211675. PMID: 41227321. - **Tsai 2021.** _Upregulating sirtuin 6 ameliorates glycolysis, EMT and distant metastasis of pancreatic adenocarcinoma with krüppel-like factor 10 deficiency._ Experimental & Molecular Medicine, 2021. DOI: 10.1038/s12276-021-00687-8. PMID: 34702956. - **Chen 2015.** _Single Nucleotide Polymorphisms of the Sirtuin 1 (SIRT1) Gene are Associated With age-Related Macular Degeneration in Chinese Han Individuals._ Medicine, 2015. DOI: 10.1097/MD.0000000000002238. PMID: 26656366. - **Shi 2020.** _Statin suppresses sirtuin 6 through miR-495, increasing FoxO1-dependent hepatic gluconeogenesis._ Theranostics, 2020. DOI: 10.7150/thno.49770. PMID: 33052223. - **Nyarady 2020.** _Effects of perinatal factors on sirtuin 3, 8-hydroxy-2′- deoxyguanosine, brain-derived neurotrophic factor and serotonin in cord blood and early breast milk: an observational study._ International Breastfeeding Journal, 2020. DOI: 10.1186/s13006-020-00301-z. PMID: 32552911. - **Budziak 2025.** _Can Sirtuin 1 Serve as a Therapeutic Target in Pulmonary Arterial Hypertension? A Comprehensive Review._ Molecules, 2025. DOI: 10.3390/molecules30183740. PMID: 41011644. - **Biscetti 2024.** _Evaluation of sirtuin 1 as a predictor of cardiovascular outcomes in diabetic patients with limb-threatening ischemia._ Scientific Reports, 2024. DOI: 10.1038/s41598-024-78576-z. PMID: 39506067. - **Sugishita 2024.** _Nicotinamide Adenine Dinucleotide (NAD)-Dependent Protein Deacetylase, Sirtuin, as a Biomarker of Healthy Life Expectancy: A Mini-Review._ Current Aging Science, 2024. DOI: 10.2174/0118746098319674240827104612. PMID: 39377386. - **Krekora 2026.** _Sirtuin 1 is a key molecular link between cellular senescence and heart failure._ Frontiers in Molecular Medicine, 2026. DOI: 10.3389/fmmed.2026.1818104. PMID: 42125493. - **Noureldein 2015.** _Fenofibrate reduces inflammation in obese patients with or without type 2 diabetes mellitus via sirtuin 1/fetuin A axis._ Diabetes Res Clin Pract, 2015. DOI: 10.1016/j.diabres.2015.05.043. PMID: 26105582. ### Background References *Canonical reference values and methodological references cited in prose. Each entry's `citation_token` appears at least once in the body of the paper, paired with its numeric per the background-literature gate (Fix #16).*
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"title": "Research Synthesis: Sirtuin Intervention Aging Effects"
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