Sirtuins Explained: SIRT1 to SIRT7

The sirtuins have had the most eventful twenty-five years of any enzyme family in ageing research. They arrived as the molecular explanation for why calorie restriction extends life, acquired a plant compound that supposedly activated them, generated a biotech acquisition, and then had two of their central claims publicly dismantled — once by a multi-laboratory replication effort and once by a pharmacology group showing that the activation assay had been measuring the wrong thing.

What survived is still substantial: seven real enzymes with well-characterised chemistry, a genuine dependence on NAD⁺, and a long list of documented substrates. This guide covers what they are, the unusual reaction they run, which claims held up, which did not, and what the honest connection is between sirtuins and the compounds sold alongside them.

What sirtuins are

Sirtuins are enzymes that strip acyl groups off lysine residues in other proteins. The name descends from yeast Sir2 — silent information regulator 2 — and the mammalian family members are its homologues.

They are conventionally called the class III histone deacetylases, which places them in the broader HDAC taxonomy, but a 2024 review of the field uses the more accurate description: NAD⁺-dependent protein deacylases. The shift from deacetylase to deacylase matters, because several family members remove groups other than acetyl, and histones are far from their only substrates.

What makes them distinctive among deacetylases is the NAD⁺ requirement. That is what ties them to cellular metabolic state, and it is the entire basis for the idea that they translate nutrient availability into changes in gene expression and protein function. Our guide to NAD+, NMN and nicotinamide riboside covers the coenzyme side.

The reaction, and why NAD⁺ is consumed

This is the single most commonly misstated fact about sirtuins, and it is worth being precise.

The reaction takes an acyl-lysine and NAD⁺ and produces three things: the deacylated substrate, nicotinamide, and 2′-O-acetyl-ADP-ribose. NAD⁺ is cleaved. It is therefore a co-substrate, consumed stoichiometrically, one molecule per deacetylation — not a cofactor that is used catalytically and handed back.

Two foundational papers established this in 2000. Imai, Armstrong, Kaeberlein and Guarente reported in Nature that the transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. In PNAS the same year, Landry and colleagues showed that SIR2-family members catalyse an NAD–nicotinamide exchange reaction requiring acetylated lysines, with an absolute requirement for NAD, which distinguished them from the deacetylases known at the time; the same paper found no evidence of histone ADP-ribosylation, contradicting an earlier report. Smith and colleagues, also in PNAS, showed the NAD⁺ requirement is phylogenetically conserved, with purified Sir2 proteins from yeast, archaea, bacteria and humans all requiring it.

The seven, and what each does

Two caveats on that table. First, localisation varies with cellular conditions and the shuttling of SIRT1 and SIRT2 is well documented, so “SIRT1 is a nuclear enzyme” is a simplification. Second, SIRT4’s ADP-ribosyltransferase activity should be read as originally reported and since reframed rather than as current consensus; the SIRT6 claim rests on firmer ground.

The lifespan claims, and the replication failure

The sirtuin-longevity story began in yeast and held there. Kaeberlein, McVey and Guarente reported in Genes & Development in 1999 that Sir2p is a limiting component of yeast longevity: increasing SIR2 gene dosage extends replicative lifespan in wild-type cells. They described two mechanisms — one involving the SIR2/3/4 complex and mating-type information, one in which Sir2p directly represses recombination caused by a replication block in the ribosomal DNA. That result is not in dispute.

What happened next is one of the more instructive episodes in modern biology. In 2001, Tissenbaum and Guarente reported in Nature that increased dosage of a sir-2 gene extends lifespan in C. elegans, with an effect of up to 50% acting upstream of daf-16. Similar claims followed in Drosophila. Together they turned sirtuins from a yeast curiosity into a general theory of ageing.

In 2011, a large multi-laboratory group led by Burnett and colleagues published, also in Nature, under the title “Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila“. Their findings, in summary: outcrossing a high-level sir-2.1 overexpression line removed the longevity increase even though the overexpression itself persisted, and the longevity instead tracked a second-site mutation affecting sensory neurons; outcrossing a separate low-copy line removed the effect too. In flies, a widely used overexpression strain did outlive wild-type controls as previously reported but did not outlive the appropriate transgenic controls, and a newer line with stronger overexpression showed no extension. Dietary restriction extended fly lifespan independently of dSir2. The authors stressed controlling for genetic background and for the mutagenic effects of transgene insertion, and did not rule out a sirtuin role in metazoan lifespan — they questioned the robustness of the earlier findings.

The resveratrol problem

In 2003, Howitz and colleagues published in Nature that small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. The most famous of those molecules was resveratrol, and the finding launched both a supplement category and a company.

In 2010, a group at Pfizer published a paper in the Journal of Biological Chemistry whose title is the argument: “SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1”. What they found was specific and damaging. With native protein substrates — full-length p53 and acetyl-CoA synthetase 1 — none of the four compounds produced apparent SIRT1 activation. The compounds did activate SIRT1 when assayed with a fluorophore-labelled peptide substrate. Biophysical methods indicated the compounds bind directly to the fluorophore-containing peptides. A control peptide lacking the fluorophore showed no activation. In other words the apparent activation was a property of the assay reagent, not of the enzyme. The same paper reported that SRT1720 did not lower plasma glucose or improve mitochondrial capacity in high-fat-diet-fed mice.

The rebuttal came in 2013, in Science: Hubbard and colleagues argued for a common allosteric mechanism in which activation depends on hydrophobic motifs in the substrate, motifs present in natural substrates such as PGC-1α and FOXO3a, with a single residue, Glu230, in SIRT1’s N-terminal domain critical for activation by every previously reported activator scaffold. In cells reconstituted with activation-defective SIRT1, the compounds’ metabolic effects were blocked.

That is a genuinely clever resolution: substrate-dependence explains both the artefact and a real mechanism. But it is not a closed case. The most recent review we verified, from 2024, describes resveratrol as a reported SIRT1 activator whose observations have been contested, refers to continuing debates about the legitimacy of direct activation, and says structural work deconvolutes some of the controversies. It also notes that SRT1460, SRT1720 and SRT2183 have off-target interactions with numerous receptors, enzymes, transporters and ion channels. Worth knowing when weighing the exchange: the senior author of the 2013 rebuttal is also the senior author of the 2003 paper under challenge.

SIRT1 and FOXO

One of the best-documented sirtuin functions is deacetylating the FOXO family of transcription factors, and this is where the family connects to something in a peptide catalogue.

Three 2004 papers established it. Brunet and colleagues published “Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase” in Science; Motta and colleagues published “Mammalian SIRT1 represses forkhead transcription factors” in Cell; and van der Horst and colleagues, in the Journal of Biological Chemistry, addressed FOXO4 specifically. That last paper has the most detailed mechanism, and it is worth stating in full because the title is often misquoted: FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). What it reports is that FOXO transcription factors are reversibly acetylated; that CBP binds and acetylates FOXO, inhibiting its transcriptional activity, with CBP binding increasing after peroxide stress; and that SIRT1 binds FOXO and deacetylates it, preventing acetylation-mediated inhibition and prolonging expression of FOXO-dependent stress-regulating genes.

SIRT1 also deacetylates PGC-1α, the coactivator that appears throughout metabolic signalling — Rodgers and colleagues reported in Nature in 2005 that nutrient control of glucose homeostasis operates through a complex of PGC-1α and SIRT1.

Does NAD⁺ really decline with age?

The chain of reasoning behind most NAD⁺ marketing is: NAD⁺ declines with age, sirtuins need NAD⁺, therefore sirtuin activity falls with age, therefore raising NAD⁺ restores it. Every link in that chain is weaker than the conclusion implies, and the first one is the weakest.

A 2022 review in Nutrients is devoted to the question, under the title “Age-Dependent Decline of NAD⁺ — Universal Truth or Confounded Consensus?”. Its findings are worth setting out:

The review warns against what it calls the poor-founded perpetuation of the idea that NAD⁺ levels universally decrease with age, describing that framing as misleading, and flags potential publication bias against papers reporting no change.

And the second link is weaker still: we found no source that measured sirtuin activity against age-related NAD⁺ levels in humans at all. The causal chain from falling NAD⁺ to falling sirtuin activity to the features of ageing is, in humans, unverified at every step.

What happened in human trials

Sirtuin activators did reach people, in two studies worth knowing about.

Libri and colleagues published a pilot randomised, placebo-controlled, double-blind phase I trial of SRT2104 in elderly volunteers in PLOS ONE in 2012. Over 28 days the compound was generally safe and well tolerated; exposure increased less than dose-proportionally; serum cholesterol, LDL and triglycerides decreased; oral glucose tolerance showed no significant change; and magnetic resonance spectroscopy showed only trends toward faster post-exercise recovery. The authors concluded the drug could be given safely to older adults with effects consistent with SIRT1 activation. It is a pilot phase I study: hypothesis-generating, not evidence of benefit.

The phase II study is more informative. Baksi and colleagues randomised 227 people with type 2 diabetes on stable metformin to SRT2104 or placebo for 28 days, publishing in the British Journal of Clinical Pharmacology in 2014. The primary objectives were safety and pharmacokinetics rather than glycaemic efficacy, and the result on glucose was null: no consistent, dose-related changes in fasting or postprandial glucose, insulin, HbA1c or fructosamine, with the few significant differences appearing to reflect an unexpected decline in the placebo arm. Pharmacokinetics were highly variable, and exposure at the highest dose was well below levels efficacious in mice, which the authors blamed for the null result. Lipids improved modestly and weight fell significantly in two dose groups.

The bottom line from the most recent review we verified is unambiguous: no sirtuin activator or inhibitor is approved by any regulator, SRT2104 was well tolerated but exhibited poor oral bioavailability in phase I, and later trials showed inter-subject variability in drug exposure and mixed outcomes. Our guide to clinical trial phases covers why a null phase II attributed to poor exposure is a genuinely ambiguous result rather than a clean negative.

The NAD⁺ precursor trials are a separate literature with a similar shape. A 2022 review found that nicotinamide riboside reliably raises NAD⁺ — one trial of 133 people reported whole-blood increases of 22 to 142% — but that a 12-week trial in obese men found skeletal muscle NAD⁺ no different from placebo despite elevated urinary metabolites, that clinical findings were mixed and mostly unreplicated, and that several trials in obese or insulin-resistant men found no change in insulin sensitivity, mitochondrial function, HbA1c or body weight. Critically for this article: the review attributes no observed benefit to sirtuin activation, and none of the trials measured sirtuin activity.

Where peptides fit — and where they don’t

NAD⁺: the real connection

The honest link between sirtuins and anything in a research catalogue runs through NAD⁺, because sirtuins consume it. That is enzymology, not marketing. What does not follow is that supplying NAD⁺ raises sirtuin activity in a person, for the reasons in the section above.

MOTS-c: the relationship runs the other way

MOTS-c is often described as activating sirtuins. The verified relationship is the reverse. A 2023 review in the Journal of Translational Medicine reports that SIRT1/PGC-1α plays a key role in the increase of MOTS-c expression due to exercise, and that the SIRT1–PGC-1α pathway mediates the production and secretion of MOTS-c in skeletal muscle. So SIRT1 sits upstream of exercise-induced MOTS-c expression. MOTS-c’s own primary mechanism in that review is the folate–AICAR–AMPK pathway, covered in our AMPK guide and our MOTS-c guide.

Epitalon: no sirtuin link exists

Epitalon, the AEDG tetrapeptide, is sometimes grouped with sirtuins in the general anti-ageing category. The most recent dedicated review of it, published in 2026, does not mention sirtuins, SIRT1, SIRT6 or NAD⁺ anywhere, and searching for a primary link returns only vendor pages. There is no published connection, and we are not going to invent one. What that review does attribute to the peptide is telomerase and telomere work, circadian and neuroendocrine effects, and reduced p16 and p21 in stem cells — while concluding that no adequately powered randomized trial has established therapeutic efficacy and describing the peptide as biologically active but clinically unproven. Our guides to Epitalon and telomeres and telomerase cover that evidence.

FOXO4-DRI: adjacent, not connected

As above: SIRT1 deacetylates FOXO4 the transcription factor. FOXO4-DRI is a separate molecule designed to disrupt a different interaction, FOXO4 with p53, and no source links it to sirtuins. The shared name is the only connection.

What’s established and what isn’t

Sourcing NAD⁺ and related reagents in Canada

The reagents in this area are a mix of peptides and non-peptides, and the right documentation differs accordingly.

• Match the analysis to the molecule. A peptide such as FOXO4-DRI or MOTS-c is characterised by HPLC purity and a mass-spectrometry identity check; a coenzyme like NAD⁺ is a different analytical problem. See reading an HPLC chromatogram and reading a mass spectrum.
• Match the batch number on the certificate to the vial. Our COA guide covers what else a useful certificate contains.
• Account for net peptide content on the peptides — labelled mass includes counter-ions and water, as our guide to net peptide content explains.
• Store cold, dry and dark, lyophilized until needed; long modified peptides such as FOXO4-DRI are the least forgiving. See the storage guide, what lyophilized means and how peptides degrade.

NAD+The co-substrate sirtuins consume, one molecule per reactionView product FOXO4-DRITargets FOXO4 and p53; no published sirtuin connectionView product MOTS-cSIRT1 sits upstream of its exercise-induced expression, not downstreamView product

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