RESEARCH MONOGRAPH · KDC-MN-301

SRT2104

May 9, 2026 Kodiac biolabs Research Revised May 30, 2026 2 min read

Our opinion on this compound

58/100

Sirtris's lead SIRT1 activator that survived the Sirtuin Drama and got a respectable phase 2 footprint, but the field has moved on

SRT2104 was the Sirtris/GSK SIRT1 activator that came out of the wreckage of the post-2010 sirtuin field correction, when the controversy over whether the Sirtris STAC compounds were directly activating SIRT1 or just hitting an artifact of the fluorogenic substrate assay played out in the literature. The eventual consensus, after a lot of papers from the Sinclair group and the counterarguments from Roy/Auwerx and others, was that the STACs do allosterically activate SIRT1 against natural substrates but the activation is more nuanced and substrate-dependent than the original assay suggested. SRT2104 was the cleanest of the second-generation STACs in terms of selectivity and pharmacokinetics.

The clinical work that GSK ran is more substantial than people remember. Multiple phase 1 and phase 2 trials in psoriasis, type 2 diabetes, ulcerative colitis, and other inflammatory indications, with mixed but not entirely null results. The metabolic phase 2 data showed modest improvements in lipid profiles and some inflammatory markers; the dermatology data was a near-miss; the type 2 diabetes data was disappointing in terms of glycemic control but did show some interesting downstream metabolic markers. Nothing pushed past phase 2 into a registrational program.

What we like: as a research tool for studying SIRT1-dependent pathways, SRT2104 is genuinely useful and well-characterized. The published phase 1/2 data give you a reasonable pharmacokinetic and safety reference. The selectivity for SIRT1 over the other sirtuins is okay.

What we dont love is the broader sirtuin enthusiasm has cooled. Sirtris was acquired by GSK for $720M in 2008, GSK shut Sirtris down in 2013, and the molecular target has not produced a clinical breakthrough at the scale the early hype suggested. The field has shifted toward NAD+ supplementation (nicotinamide riboside, nicotinamide mononucleotide) where the mechanism is more tractable, and toward direct sirtuin activators that work via different mechanisms.

Sourcing for SRT2104 research material is okay but not great. The molecule is well-characterized, available from research suppliers, and HPLC purity is reliable. Cost-per-gram is higher than most small molecules in the longevity research space.

Evidence: 55
Mechanism: 60
Reliability: 55
Safety: 75
Sourcing: 65
Value: 50
Signal: 50
Staying power: 50

Plain-language summary Intrigue 50 / 100

SRT2104 is a small-molecule sirtuin 1 (SIRT1) activator developed at Sirtris Pharmaceuticals (later acquired by GSK). It was designed as a more potent and drug-like successor to resveratrol, the natural compound that started the sirtuin-aging story. Sirtuins are NAD+-dependent enzymes that deacetylate metabolic and stress-response targets, hypothesized to mediate calorie-restriction-like longevity effects. SRT2104 activates SIRT1 allosterically and produced metabolic and inflammatory benefits in mouse studies. Phase 2 trials in diabetes, ulcerative colitis, and cardiovascular disease showed modest signals at best, and GSK shut down Sirtris in 2013 amid skepticism about the sirtuin-activator concept. Of mainly historical interest as a flagship compound of a faded program. Not stocked by Kodiac. This monograph is provided for research and educational reference.

Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

Selective SIRT1 activator

A small-molecule selective sirtuin 1 (SIRT1) activator developed for diabetes, ulcerative colitis, and cardiovascular disease.

Abstract

SRT2104 (CAS 1093403-33-8; molecular formula C25H23N5O2S; molecular weight 457.55) is a small-molecule selective sirtuin 1 (SIRT1) activator developed at Sirtris Pharmaceuticals (GSK). The compound was designed as a successor to resveratrol with substantially higher potency at SIRT1 and improved drug-like properties. Mechanism: allosteric SIRT1 activation, increasing NAD+-dependent deacetylation of substrates including p53, FOXO3, NF-kB, and PGC-1-alpha; downstream effects include enhanced mitochondrial biogenesis, reduced inflammation, and improved metabolic homeostasis in mouse models. Phase 2 trials in psoriasis, type 2 diabetes, and cardiovascular outcomes have shown modest or inconclusive effects. Plasma half-life supports daily oral dosing. Used as a reference SIRT1 activator in academic longevity research.

Mechanism of action

Small-molecule allosteric SIRT1 activator; increases NAD+-dependent deacetylation of multiple metabolic and stress-response substrates.

Reported research dose ranges

Trial doses 250 to 2000 mg in the published literature. Mouse studies 10 to 100 mg/kg.

References

Hubbard BP, et al. Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 2013.
Libri V, et al. A pilot randomized, placebo-controlled clinical trial to investigate the effects of SRT2104 in healthy elderly subjects. PLoS ONE 2012.
Venkatasubramanian S, et al. Cardiovascular effects of a novel SIRT1 activator, SRT2104, in otherwise healthy cigarette smokers. J Am Heart Assoc 2013.

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KDC-MN-301

The full reference document is provided strictly for research use only. It reports research dose ranges from the published literature, not instructions for use in humans or animals.

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FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

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SRT2104

Abstract

Mechanism of action

Reported research dose ranges

References

Read the full monograph

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Abstract

Mechanism of action

Reported research dose ranges

References

Read the full monograph

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