Sirtuins in Ageing and Disease

Sirtuins are a family of NAD+ dependent enzymes with histone deacetylase activity — the mammalian homologues of the yeast Sir2 (Silent Information Regulator 2) gene.

Because they require NAD+, sirtuins act as cellular energy sensors — activated when the NAD+/NADH ratio is high, i.e. in caloric restriction, fasting and exercise.

Seven human isoforms (SIRT1–SIRT7): SIRT1, SIRT6 and SIRT7 are mainly nuclear; SIRT2 is cytoplasmic; SIRT3, SIRT4 and SIRT5 are mitochondrial.

SIRT1 and SIRT6 are the two most relevant to ageing. Sirtuins regulate genomic stability, lifespan, energy metabolism and tumorigenesis.

NAD+ levels fall progressively with age, reducing sirtuin activity — the central link between metabolism and ageing.

Sirtuins are the molecular mediators of caloric restriction. Dietary restriction extends lifespan by exerting multiple effects on chromatin through sirtuins, TOR and other factors.

This makes ageing partly an epigenetic phenomenon — sirtuins act by deacetylating histones and non-histone proteins, altering gene expression without changing the DNA sequence.

SIRT1 targets include p53, FOXO transcription factors, NF-kappaB and PGC-1alpha — linking sirtuins to apoptosis, stress resistance, inflammation and mitochondrial biogenesis.

SIRT6 maintains chromatin structure at telomeres by deacetylating histone H3 lysine 9, preventing telomeric DNA damage and cellular senescence. SIRT6-deficient mice show genomic instability and premature ageing, and SIRT6 is upregulated during caloric restriction.

SIRT1 and SIRT6 act synergistically — SIRT1 deacetylates SIRT6 at residue K33, and deacetylated SIRT6 then remodels chromatin.

Anti-inflammatory action: SIRT1, SIRT2 and SIRT6 inhibit NF-kappaB signalling, reducing the cytokine output that drives inflammageing.

Mitochondrial sirtuins (SIRT3–5) regulate oxidative metabolism and reduce ROS — relevant to sarcopenia and frailty. Evidence — The Rise and Fall of the Sirtuin Hypothesis (key discrimination point)

Initial excitement: activation of a sirtuin was found to extend lifespan in yeast, generating intense interest in sirtuins as "longevity genes".

Subsequent reversal: the sirtuin story then unravelled — those experiments were not replicated by other laboratories. (Science 2011)

Current textbook position: in mice, modulation of sirtuins does NOT extend lifespan, but it does expand healthspan — less diabetes mellitus, healthier metabolic profiles and healthier livers.

Resveratrol, a molecule from red wine acting through a sirtuin, extended lifespan in worms and flies, but these findings were also not confirmed elsewhere. It may extend healthspan rather than lifespan.

Sirtuins sit within deregulated nutrient sensing, one of the antagonistic hallmarks of ageing. The other arms are the insulin/IGF-1 axis, mTOR and AMPK.

Reduced insulin/IGF-1 and mTOR signalling is associated with longevity. Intense trophic and anabolic activity accelerates ageing; downregulation is a defensive response.

Rapamycin (mTOR inhibitor) extended lifespan in genetically heterogeneous mice even when started in late life; the practical barrier to human use is immunosuppression.

Metformin is a potential anti-ageing drug because of its effects on deregulated nutrient sensing, mitochondrial dysfunction, DNA damage and inflammation. It has since been shown to be a direct SIRT1-activating compound.

Clinical bottom line: caloric restriction is not practical in humans, so research has shifted to caloric-restriction mimetics — sirtuin activators, rapalogs, metformin and NAD+ precursors.

Cautionary note: resetting the epigenome carries a risk of malignancy in cells that have already accumulated mutations and then acquire increased proliferative potential.

SIRT1 and SIRT6 consolidated as the ageing sirtuins. Sirtuins are framed as NAD+ dependent enzymes regulating genomic stability, lifespan, energy metabolism and tumorigenesis, with SIRT1 and SIRT6 specifically regulating ageing-related signalling at molecular, cellular, tissue and whole-organism levels. Name SIRT6 if asked for the single most important anti-ageing sirtuin — it protects telomeric chromatin and its loss causes progeria in mice. (Ageing Res Rev / Cellular Signalling 2023)

The SIRT7 paradox — not all sirtuins are pro-longevity. While SIRT1 and SIRT6 are predominantly anti-inflammatory, SIRT7 can be pro-inflammatory in a tissue-specific manner under physiological stress; recent in vivo evidence shows SIRT7 knockout mice have a longer lifespan and delayed onset of age-related conditions. This overturns the simple "sirtuins = longevity genes" model. (Narrative review 2026)

Direct sirtuin activators have replaced resveratrol. Resveratrol's supposed SIRT1 activation was an assay artefact. Attention has moved to cellularly active SIRT6 allosteric activators: MDL-800 improves genomic stability and pluripotency of aged murine iPS cells, and pyrrolo[1,2-a]quinoxaline derivatives have been developed as potent, selective SIRT6 activators. (Exploration of Drug Science 2025)

NAD+ precursors (NR and NMN) — biochemically effective, clinically disappointing. In a 12-week double-blind RCT of nicotinamide riboside 500 mg twice daily in 52 older adults with amnestic MCI, blood NAD+ approximately doubled (23.4 to 48.5 micromol/L) and left hippocampal perfusion increased significantly — but cognitive function did not significantly improve. A systematic review of NMN trials found a significant effect on raising NAD+ yet most clinically relevant metabolic outcomes did not differ from control. A further meta-analysis concluded evidence for NMN and NR effects on skeletal muscle mass and function in older adults remains inconclusive. (Crit Rev Food Sci Nutr 2025; J Cachexia Sarcopenia Muscle 2025)

Practical message. No sirtuin-targeted agent is licensed for any ageing indication. The interventions with proven benefit on the same nutrient-sensing pathways remain exercise, dietary modification and weight management — and metformin where indicated for diabetes.