Research Synthesis: Sirtuin Effects

Research Synthesis: Sirtuin Effects

Abstract

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.

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.

The sirtuin family of NAD+-dependent deacylases has been implicated in cardiometabolic health, inflammation, and longevity, yet whether modulating their expression or activity yields clinically meaningful benefit remains unresolved (Wu 2022; Lee 2019).

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.

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).

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.

Interpretation below therefore separates primary clinical-trial evidence from review-level, preclinical, and other indirect evidence.

Methods

Review type and protocol

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.

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: 2026-06-04.

Search strategy

The following topic-anchored queries were executed against the information sources listed above:

• sirtuin effects aging
• sirtuin effects older adults
• sirtuin effects randomized controlled trial
• sirtuin aging
• sirtuin older adults
• sirtuin randomized controlled trial

Eligibility criteria

• Sources whose primary content addresses sirtuin 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 196 records in the receipt-candidate union, 76 were classified as source candidates and 39 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	196
Classified source candidates	76
No extractable claims	49
None-only claim binding	9
Mixed partial-or-none claim-binding candidates	49
Partial-only claim-binding candidates	6
Strict high-confidence sources	7
Admitted final sources	39

Exclusion reasons

• Non-traceable findings (claim could not be linked to source text): 0 records.
• Wrong population / off-topic sources excluded at screening.
• Duplicate records deduplicated by DOI / PMID before screening.

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 appraisal, and claim registry) rather than from re-parsed full text.

Risk-of-bias appraisal

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.

Synthesis approach

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.

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. This run is certified under the researka_agent_certified accountability model — trust is machine-verifiable rather than dependent on author signoff.

Results

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.

Evidence domain	Corpus slice	Strongest signal	Directness	Main limitation
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
Cardiometabolic	n=6; claims=328	no extracted directional signal in 4/6 sources	5 indirect; 1 review	limited corpus depth in this outcome class
Dosing and Pharmacokinetics	n=4; claims=105	no extracted directional signal in 4/4 sources	2 indirect; 2 review	limited corpus depth in this outcome class
Immune and Inflammation	n=3; claims=109	no extracted directional signal in 3/3 sources	2 indirect; 1 mechanistic	limited corpus depth in this outcome class
Population / prevalence	n=2; claims=31	no extracted directional signal in 2/2 sources	2 indirect	limited corpus depth in this outcome class
Immune	n=2; claims=31	no extracted directional signal in 1/2 sources	1 mechanistic; 1 review	limited corpus depth in this outcome class
Longevity	n=1; claims=2	unclear signal in 1/1 sources	1 indirect	single-source slice; hypothesis-generating
Muscle Function	n=1; claims=38	no extracted directional signal in 1/1 sources	1 indirect	single-source slice; hypothesis-generating

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

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.

Cardiometabolic Outcomes

6 included sources were assigned to this outcome class. Directional coding: null=4, unclear=2. Directness coding: indirect=5, review=1.

Dose / exposure Outcomes

4 included sources were assigned to this outcome class. Directional coding: null=4. Directness coding: indirect=2, review=2.

Immune Inflammation Outcomes

3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=2, mechanistic=1.

Population / prevalence Outcomes

2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=2.

Immune Outcomes

2 included sources were assigned to this outcome class. Directional coding: negative=1, null=1. Directness coding: mechanistic=1, review=1.

Longevity Outcomes

1 included source were assigned to this outcome class. Directional coding: unclear=1. Directness coding: indirect=1.

Muscle Function Outcomes

1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=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.

The curated corpus is weighted toward short-term biomarker and mechanistic endpoints, with no long-term mortality or hard-cardiovascular-outcome randomized trial included. Without a trial powered for all-cause mortality, major adverse cardiac events, or hospitalization, the headline anti-aging claim for sirtuin modulation remains untestable against hard outcomes. This absence constitutes the most consequential gap: the synthesis can describe expression-level shifts but cannot adjudicate whether those shifts translate into clinically meaningful survival benefits.

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.

The human studies in this corpus are restricted to narrow demographic slices that limit external validity. Paediatric populations, non-diabetic middle-aged adults, and individuals of non-European ancestry are effectively absent from the corpus. Moreover, the preclinical sources — including Shen 2019 (C57BL/6 mice, n = 6 per group) and Liu 2021 (aged-mouse neuroinflammation model) — use rodent strains that may not recapitulate human sirtuin biology across the lifespan, further narrowing the population to whom mechanistic findings can be generalized.

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.

Conclusion

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.

What This Synthesis Adds

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.

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.

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.

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.

Boundary-Condition Matrix

Evidence domain	Direct sources	Indirect / mechanism sources	Direction profile	Interpretation boundary
cardiometabolic	0	6	null, unclear	direct interventional hard-endpoint gap
immune	0	2	negative, null	direct interventional hard-endpoint gap
longevity	0	1	unclear	direct interventional hard-endpoint gap
muscle function	0	1	null	direct interventional hard-endpoint gap
deficiency prevalence	0	2	null	direct interventional hard-endpoint gap
dosing and pharmacokinetics	0	4	null	direct interventional hard-endpoint gap
immune and inflammation	0	3	null	direct interventional hard-endpoint gap
contextual adjacent evidence	1	19	null, positive	conflict-resolution gap

Evidence-Gap Priority

Priority	Gap	Rationale
P1	cardiometabolic: direct interventional hard-endpoint gap	0 direct and 6 indirect sources; direction profile: null, unclear
P2	immune: direct interventional hard-endpoint gap	0 direct and 2 indirect sources; direction profile: negative, null
P3	longevity: direct interventional hard-endpoint gap	0 direct and 1 indirect source; direction profile: unclear
P4	muscle function: direct interventional hard-endpoint gap	0 direct and 1 indirect source; direction profile: null
P5	deficiency prevalence: direct interventional hard-endpoint gap	0 direct and 2 indirect sources; direction profile: null

Next-Study Design Recommendation

The next high-yield study for Sirtuin Effects should target the cardiometabolic 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

• Werida 2023; RCT (clinical); tier=A1; directness=direct; N=—; population=type 2 diabetes patients; endpoint=contextual adjacent evidence; direction=positive; representative statistic=P < 0.001.
• Noureldein 2015; Review / meta-analysis; tier=B1; directness=review; N=—; population=type 2 diabetes patients; endpoint=immune; direction=negative; representative statistic=P < 0.001.
• Nowak-Szwed 2025; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=cardiometabolic; direction=unclear; representative statistic=P < 0.001.
• Garcia-Martinez 2023; Observational; tier=B2; directness=indirect; N=—; population=type 2 diabetes patients; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.05.
• Wu 2022; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=cardiometabolic; direction=unclear.
• Nikooyeh 2021; Observational; tier=B2; directness=indirect; N=—; population=type 2 diabetes patients; endpoint=cardiometabolic; direction=null; representative statistic=P < 0.001.
• Wasserfurth 2021; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual adjacent evidence; direction=null; representative statistic=P = 0.004.
• Davari 2020; Observational; tier=B2; directness=indirect; N=—; population=type 2 diabetes patients; endpoint=dosing pharmacokinetics; direction=null; representative statistic=P = 0.008.
• Fu 2022; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=immune inflammation; direction=null.
• Hwang 2020; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.01.

Source Classification Map

Each retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement.

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 mechanism vs clinical: Werida 2023 vs Liu 2021; Werida 2023 (contextual other, direct) vs Liu 2021 (immune inflammation, mechanistic)

• Severity 4 mechanism vs clinical: Werida 2023 vs Cao 2022; Werida 2023 (contextual other, direct) vs Cao 2022 (immune, mechanistic)
• Severity 3 null vs positive: Garcia-Martinez 2023 vs Werida 2023; Garcia-Martinez 2023 (null) vs Werida 2023 (positive) on contextual other
• Severity 3 null vs positive: Werida 2023 vs Patyal 2024; Werida 2023 (positive) vs Patyal 2024 (null) on contextual other
• Severity 3 null vs positive: Werida 2023 vs Sayedyousef 2025; Werida 2023 (positive) vs Sayedyousef 2025 (null) on contextual other
• Severity 3 null vs positive: Werida 2023 vs Jagodzinska 2025; Werida 2023 (positive) vs Jagodzinska 2025 (null) on contextual other
• Severity 3 null vs positive: Werida 2023 vs Moin 2026; Werida 2023 (positive) vs Moin 2026 (null) on contextual other
• Severity 3 null vs positive: Werida 2023 vs Gavia-Garcia 2026; Werida 2023 (positive) vs Gavia-Garcia 2026 (null) on contextual other

Additional corpus sources included animal/preclinical evidence; additional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Hajighasem 2018, Cho 2022, Roggerio 2018, Daneshi-Maskooni 2017, Gonzalez-Fernandez 2019, Martinez-Iglesias 2022, Ding 2021, Rigdon 2024, Bodis 2019, Liu 2019, Lilja 2021, Aghasi 2018, Bo 2018, Zhang 2018, Tsai 2021, Shao 2019, Shi 2020, Nyarady 2020, Wan 2022, Biscetti 2024.

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.
• 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.
• 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.
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• 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.
• Fu 2022. p53/sirtuin 1/NF-κB Signaling Axis in Chronic Inflammation and Maladaptive Kidney Repair After Cisplatin Nephrotoxicity. Frontiers in Immunology, 2022. DOI: 10.3389/fimmu.2022.925738. PMID: 35874713.
• Shen 2019. Myricanol rescues dexamethasone‐induced muscle dysfunction via a sirtuin 1‐dependent mechanism. Journal of Cachexia, Sarcopenia and Muscle, 2019. DOI: 10.1002/jcsm.12393. PMID: 30793539.
• Liu 2021. Sirtuin 3 protects against anesthesia/surgery-induced cognitive decline in aged mice by suppressing hippocampal neuroinflammation. Journal of Neuroinflammation, 2021. DOI: 10.1186/s12974-021-02089-z. PMID: 33541361.
• 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.
• Hajighasem 2018. Effects of resveratrol, exercises and their combination on Farnesoid X receptor, Liver X receptor and Sirtuin 1 gene expression and apoptosis in the liver of elderly rats with nonalcoholic fatty liver. PeerJ, 2018. DOI: 10.7717/peerj.5522. PMID: 30221089.
• 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.
• 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.
• Cao 2022. Sirtuin 3 Dependent and Independent Effects of NAD + to Suppress Vascular Inflammation and Improve Endothelial Function in Mice. Antioxidants, 2022. DOI: 10.3390/antiox11040706. PMID: 35453391.
• 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. DOI: 10.1155/jdr/5528647. PMID: 41624996.
• Martinez-Iglesias 2022. Nosustrophine: An Epinutraceutical Bioproduct with Effects on DNA Methylation, Histone Acetylation and Sirtuin Expression in Alzheimer’s Disease. Pharmaceutics, 2022. DOI: 10.3390/pharmaceutics14112447. PMID: 36432638.
• Ding 2021. Sirtuin 2 knockdown inhibits cell proliferation and RAS/ERK signaling, and promotes cell apoptosis and cell cycle arrest in multiple myeloma. Molecular Medicine Reports, 2021. DOI: 10.3892/mmr.2021.12400. PMID: 34476507.
• Rigdon 2024. 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. Clinical Pharmacology in Drug Development, 2024. DOI: 10.1002/cpdd.1488. PMID: 39587867.
• Bodis 2019. Serum and follicular fluid levels of sirtuin 1, sirtuin 6, and resveratrol in women undergoing in vitro fertilization: an observational, clinical study. The Journal of International Medical Research, 2019. DOI: 10.1177/0300060518811228. PMID: 30556451.
• Liu 2019. Resveratrol inhibits parathyroid hormone-induced apoptosis in human aortic smooth muscle cells by upregulating sirtuin 1. Renal Failure, 2019. DOI: 10.1080/0886022X.2019.1605296. PMID: 31106631.
• 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.
• Patyal 2024. The Role of Sirtuin-1 Isoforms in Regulating Mitochondrial Function. Current Issues in Molecular Biology, 2024. DOI: 10.3390/cimb46080522. PMID: 39194739.
• 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.
• Zhang 2018. Crosstalk between gut microbiota and Sirtuin-3 in colonic inflammation and tumorigenesis. Experimental & Molecular Medicine, 2018. DOI: 10.1038/s12276-017-0002-0. PMID: 29650970.
• 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.
• Jagodzinska 2025. The impact of histone deacetylase inhibition on neurobehavioural outcomes in preclinical models of traumatic and non-traumatic spinal cord injury: a systematic review. Frontiers in Immunology, 2025. DOI: 10.3389/fimmu.2025.1690997. PMID: 41280930.
• Shao 2019. Improved mass spectrometry-based activity assay reveals oxidative and metabolic stress as sirtuin-1 regulators. Redox Biology, 2019. DOI: 10.1016/j.redox.2019.101150. PMID: 30877853.
• 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.
• Wan 2022. Regulation of Mitophagy by Sirtuin Family Proteins: A Vital Role in Aging and Age-Related Diseases. Frontiers in Aging Neuroscience, 2022. DOI: 10.3389/fnagi.2022.845330. PMID: 35615591.
• Lee 2019. Sirtuin signaling in cellular senescence and aging. BMB Reports, 2019. DOI: 10.5483/BMBRep.2019.52.1.290. PMID: 30526767.
• 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.
• 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 clinical thresholds 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).

• Cruz-Jentoft 2019. Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019;48(1):16-31. DOI: 10.1093/ageing/afy169. PMID: 30312372.
• Ioannidis 2005. Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124. DOI: 10.1371/journal.pmed.0020124. PMID: 16060722.