SRT-2104
SRT2104 · GSK2245840
Last updated
At a glance
Overview
Why SRT-2104 Earned Its Place in the Longevity Stack#
SRT-2104 is the most selective small-molecule SIRT1 activator ever taken into human trials — a first-in-class STAC developed by Sirtris/GSK that directly turns up the deacetylase the longevity community has been trying to coax for years with resveratrol and NAD⁺ precursors. Where NMN and NR supply the substrate, SRT-2104 activates the enzyme itself, allosterically lowering SIRT1's K_m and driving downstream PGC-1α, FOXO, and NF-κB deacetylation. The result, across multiple Phase I and II readouts, is improved lipid profiles, blunted inflammatory cytokine response, and — in mice — extended mean and maximum lifespan.
The community gravitates to it for three concrete reasons: the lipid effect (total cholesterol, LDL, and triglycerides all drop meaningfully on 1–2 g/day, useful for anyone managing on-cycle dyslipidemia), the anti-inflammatory profile (NF-κB suppression with no hepatotoxicity, hypoglycemia, or hormonal interaction across 84-day dosing), and the mitochondrial-biogenesis mechanism that pairs cleanly with NMN, rapamycin, and metformin in a serious longevity stack. It is non-hormonal, requires no PCT, and applies the same dose to male and female subjects.
"SRT2104 is the most selective small-molecule SIRT1 activator developed so far, achieving allosteric activation, regulation of metabolic and inflammatory pathways, and improvement of multiple biomarkers in clinical studies." — Wu et al., Scientific Reports (2024)
It is not a hype compound — the Phase II type-2 diabetes trial failed its primary endpoint, and SRT-2104 produces biomarker-level rather than subjective effects, so anyone chasing a "felt" stimulant response will be disappointed. The sections below cover documented SRT-2104 dosage ranges, the critical food-effect protocol (fasted dosing is effectively sub-clinical), evidence-backed use-case stacks with NMN and rapamycin, side-effect profile, and the most common sourcing and protocol mistakes seen in the longevity community.
How SRT-2104 works
Allosteric SIRT1 Activation#
SRT-2104 is the most selective small-molecule activator of SIRT1 developed to date — a first-in-class STAC (sirtuin-activating compound) structurally unrelated to resveratrol. SIRT1 is an NAD⁺-dependent class III deacetylase that strips acetyl groups off lysine residues on more than 70 known substrates, including transcription factors, metabolic regulators, and inflammatory signalling proteins.
Mechanistically, SRT-2104 does not mimic NAD⁺. It binds an allosteric site on SIRT1 and lowers the K_m for acetylated peptide substrates, increasing catalytic efficiency at physiological NAD⁺ concentrations. This is why pairing SRT-2104 with an NAD⁺ precursor (NMN, NR) is mechanistically coherent — the precursor supplies substrate, SRT-2104 activates the enzyme processing it.
"SRT2104 is the most selective small-molecule SIRT1 activator developed so far, achieving allosteric activation, regulation of metabolic and inflammatory pathways, and improvement of multiple biomarkers in clinical studies." — Wu QJ, Zhang TN, Chen HH, et al. Scientific Reports, 2024
PGC-1α and Mitochondrial Biogenesis#
SIRT1 deacetylates PGC-1α, the master regulator of mitochondrial biogenesis. Activated PGC-1α drives transcription of mitochondrial DNA, increases oxidative phosphorylation capacity, and pushes fuel selection toward fatty-acid oxidation.
In dystrophin-deficient mdx mice, SRT-2104 produced a measurable fast-to-slow myofiber phenotype shift, suppressed fibrosis, and reduced oxidative damage in skeletal muscle — exactly the pattern expected from sustained PGC-1α activation.
"SRT2104 administration induced a fast-to-slow fiber-type shift, reduced fibrosis, and suppressed oxidative damage in the skeletal muscle of mdx mice." — Kuno A, Horio Y, Oxidative Medicine and Cellular Longevity, 2016
Practical relevance: endurance-focused and hybrid-athlete users stack SRT-2104 on top of an NAD⁺ precursor specifically to lean on this pathway. Subjective endurance effects in healthy athletes are not clinically documented — this is mechanism-driven, not RCT-driven.
NF-κB Suppression and Inflammatory Tone#
SIRT1 deacetylates the p65 subunit of NF-κB, blunting transcription of TNF-α, IL-6, and IL-1β. This is the single best-characterised effect of SRT-2104 in humans. In LPS-challenged smokers, 28 days of administration suppressed inflammatory cytokine response and improved endothelial function; the psoriasis Phase IIa cohort showed PASI improvements consistent with systemic inflammation downregulation.
For physique-focused users running heavy orals or 19-nors, this is the most relevant mechanism — elevated CRP, joint inflammation, and skin reactivity on cycle all sit downstream of NF-κB signalling. SRT-2104 is used by some of the longevity-aware AAS cohort as a non-NSAID, non-glucocorticoid inflammation lever that doesn't blunt training adaptation.
Lipid Handling via LXR / SREBP-1c#
SIRT1 deacetylates LXR and modulates SREBP-1c, improving cholesterol efflux and reducing hepatic lipogenesis. This is not theoretical — it is the most reproducible biomarker effect of SRT-2104 in humans across multiple Phase I/II cohorts.
"Treatment with SRT2104 resulted in significant reductions in total cholesterol, low-density lipoprotein cholesterol, and triglycerides compared with placebo." — Venkatasubramanian S, Noh RM, Daga S, et al. Journal of the American Heart Association, 2013
Reductions in the smoker cohort: total cholesterol –11.6 mg/dL, LDL-C –10 mg/dL, triglycerides –39.8 mg/dL on 2 g/day × 28 days. The same lipid signal appeared in the T2DM Phase II despite the glucose endpoint being null. For anyone managing oral-AAS-driven dyslipidemia, this is the most directly observable effect of the compound on a blood panel.
FOXO, p53, and the Senescence Axis#
SIRT1 also deacetylates FOXO1/3 (driving oxidative-stress resistance and autophagy gene transcription) and p53 (modulating the apoptosis / senescence balance). In preclinical emphysema models, SRT-2104 reduced type-II alveolar epithelial cell senescence, providing the mechanistic rationale for the broader "anti-senescence" framing used in longevity protocols.
Combined with eNOS deacetylation — which improves endothelial nitric oxide production — this axis underpins the scalp-microcirculation and skin-quality rationale that looksmaxxing users invoke when layering SRT-2104 onto a hair/skin stack. Direct dermatology evidence remains limited to the psoriasis Phase IIa, so the anti-senescence framing is mechanism-driven rather than outcome-proven in healthy cosmetic users.
Pharmacological Behaviour That Shapes the Mechanism#
Two PK features dominate how the above mechanisms translate into real exposure:
- Food effect is enormous. Co-administration with a fat-containing meal increases AUC up to ~4× versus fasted dosing. Fasted dosing is effectively sub-clinical — none of the mechanisms above engage meaningfully without lipid co-ingestion.
- Sub-proportional PK above ~1 g. Doubling the dose does not double exposure. The dose–response curve flattens, which is why the community standard sits at 500 mg fed rather than chasing gram-scale dosing.
"SRT2104 was well tolerated across a wide range of doses, was absorbed after oral administration, and demonstrated significant food effect and less than dose-proportional pharmacokinetics." — Hoffmann E, Wald J, Lavu S, et al. British Journal of Clinical Pharmacology, 2013
The practical translation: 500 mg administered with breakfast eggs and avocado will out-perform 1500 mg administered fasted. Every mechanism on this page is gated by that single administration detail.
Protocol
| Level | Dose | Frequency | Notes |
|---|---|---|---|
| Low | 250–500 mg | Once daily | Documented entry-level range |
| Mid | 500–1000 mg | Once daily | Most commonly studied range |
| High | 1000–2000 mg | Once daily | Once-daily oral administration with a fat-containing meal (breakfast is typical). Some longevity protocols use a 5-days-on / 2-days-off cadence to limit accumulation. |
Cycle length & outcomes
Documented cycle
4–12 weeks
Plateau after
12 wks
Cycle Length & Cadence#
SRT-2104 is a non-hormonal SIRT1 activator, so cycle planning is driven by published trial durations and accumulation PK — not by HPTA suppression or receptor downregulation. No loading phase is required, and the half-life (~15–20 h) supports clean once-daily dosing.
| Goal | Cycle Length | Daily Dose | Cadence |
|---|---|---|---|
| Lipid / cardiovascular support | 4–12 weeks | 500–2000 mg | Once daily with breakfast |
| AAS-cycle inflammation adjunct | 6–8 weeks | 500–1000 mg | Once daily, paired with oral cycle |
| Mitochondrial / endurance | 8–12 weeks | 250–500 mg | Once daily, fatty pre-training meal |
| Healthspan / longevity stack | 12 weeks, 2–4×/year | 250–500 mg | 5 days on / 2 off |
| Skin / scalp anti-senescence | 8–12 weeks | 250–500 mg | Once daily with food |
Loading, Tapering & Food Effect#
No loading is needed — repeat-dose PK shows accumulation plateaus at roughly 3× single-dose exposure within the first week (Hoffmann 2013). No taper is needed at cycle end, since SRT-2104 doesn't suppress endogenous hormones or downregulate the receptor it activates.
The single non-negotiable protocol element is food pairing. Co-administration with a fat-containing meal increases AUC up to ~4× versus fasted dosing.
"SRT2104 was well tolerated across a wide range of doses, was absorbed after oral administration, and demonstrated significant food effect and less than dose-proportional pharmacokinetics." — Hoffmann et al., Br J Clin Pharmacol (2013)
Fasted administration is effectively sub-clinical exposure. Eggs, avocado, olive oil, or full-fat yoghurt at breakfast are the standard community pairing. Above ~1 g, sub-proportional PK means each additional gram delivers diminishing exposure — going from 1 g to 2 g fed is a smaller jump than the dose ratio suggests.
Onset Timing#
Unlike repair peptides where subjective effects appear within 7–10 days, SRT-2104 produces biomarker-level effects that emerge over weeks:
- Lipid panel shifts (TC, LDL, TG reductions): detectable at 28 days in trial cohorts (Venkatasubramanian 2013; Libri 2012).
- hs-CRP / inflammatory markers: typically 4–8 weeks.
- Mitochondrial / endurance adaptations: mechanism-driven, observable on the order of 8–12 weeks if at all subjectively noticeable.
Anyone running SRT-2104 expecting an acute "feel" the way they would with stimulants, NAD⁺ infusions, or peptides will be disappointed. The compound is judged by bloodwork, not by sensation.
On-Cycle Bloodwork Cadence#
Because SRT-2104's most reliable effect is the lipid signature, bloodwork is the protocol's primary feedback loop:
- Baseline: comprehensive lipid panel (TC, LDL, HDL, TG, ApoB), CMP (LFTs, glucose, creatinine), CBC, hs-CRP, HbA1c.
- Week 4: repeat lipid panel + hs-CRP. The early lipid response predicts whether the cycle is "working" at the dose chosen.
- Week 8–12 (end of cycle): full repeat of baseline panel.
- 4 weeks post-cycle: optional washout panel to see how durable the lipid shifts are off-drug.
"Treatment with SRT2104 resulted in significant reductions in total cholesterol, low-density lipoprotein cholesterol, and triglycerides compared with placebo." — Venkatasubramanian et al., JAHA (2013)
LFTs and renal markers have stayed clean across every published cohort up to 2 g/day for 28 days and 1.5 g/day for 84 days, so the bloodwork cadence is about efficacy verification, not toxicity surveillance.
"SRT2104 was safe and well-tolerated over 28 days in elderly subjects at doses up to 2.0 g, with no evidence of serious adverse events or organ toxicity." — Libri et al., PLoS One (2012)
Repeat-Cycle Structure#
No published data exists beyond 12 weeks of continuous administration. The dominant community pattern is 8–12 weeks on, 4 weeks off, repeated 2–4× per year, which aligns conservatively with the longest trial duration on record (psoriasis Phase IIa at 84 days). A minority of longevity-focused users run 5 days on / 2 days off indefinitely to limit accumulation — extrapolated from the ~3× accumulation ceiling, not from any clinical evidence. Neither schedule has a strict clinical mandate; both are defensible extensions of the available data.
Risks & mistakes
Common (most users)#
Across Phase I and Phase II trials covering single doses up to 3 g and repeat dosing up to 2 g/day for 84 days, SRT-2104 produced very few drug-attributable effects. The handful that did appear were mild and dose-related:
- Mild nausea or GI upset — most often seen at ≥1 g doses. Mitigation: administer with a substantial fat-containing meal (which is already required for absorption), and split the dose across two meals if a single 1.5–2 g morning dose is poorly tolerated.
- Headache — transient, typically resolves within the first week. Adequate hydration and electrolytes usually handle it; if persistent, step the dose back to the next tier down.
- Loose stools / diarrhoea — more frequent with suspension formulations than capsules. Capsule format is preferred for that reason.
- Transient mild fatigue at initiation — reported anecdotally in the first 3–7 days; resolves without intervention.
"SRT2104 was well tolerated across a wide range of doses, was absorbed after oral administration, and demonstrated significant food effect and less than dose-proportional pharmacokinetics." — Hoffmann E, Wald J, Lavu S, et al., British Journal of Clinical Pharmacology (2013).
Uncommon (dose-dependent or individual)#
- GI intolerance at 1.5–2 g/day — the upper end of the published range. If GI tolerance becomes the limiting factor, the protocol calls for stepping back to 1 g/day; the sub-proportional PK above ~1 g means exposure is barely improved by pushing further anyway.
- Lipid panel "over-correction" — not a true adverse effect, but worth flagging: 1–2 g/day reproducibly drops total cholesterol, LDL, and triglycerides. Subjects already on a statin, bempedoic acid, or ezetimibe should re-check lipids at the 8-week mark to confirm LDL hasn't undershot the target band.
- Sleep changes — occasional reports of altered sleep architecture or vivid dreams in community use, consistent with circadian effects of SIRT1 activation. Mitigation: shift dosing earlier in the day (breakfast is already the standard window).
- Bloodwork to track at higher tiers: baseline + 8-week comprehensive lipid panel (TC, LDL, HDL, TG, ApoB), CMP (LFTs, glucose, creatinine), CBC, hs-CRP, HbA1c. Across published trials none of these moved adversely, but the community standard is to confirm rather than assume.
"Treatment with SRT2104 resulted in significant reductions in total cholesterol, low-density lipoprotein cholesterol, and triglycerides compared with placebo." — Venkatasubramanian S, Noh RM, Daga S, et al., Journal of the American Heart Association (2013).
Rare but serious#
No serious drug-related adverse events have been reported in the published clinical record (n > 200 subjects across Phase I and Phase II, up to 84 days continuous dosing). Specifically, no signals have appeared for:
- Hepatotoxicity (LFTs unchanged across all published cohorts)
- Renal toxicity (creatinine and BUN unchanged)
- Hypoglycaemia (notably null even in the T2DM Phase II — efficacy was absent but so was glycaemic risk)
- Haematological abnormalities
- QT prolongation or cardiac conduction effects
The theoretical concern that warrants caution is tumour biology. SIRT1's role in malignancy is context-dependent — it acts as a tumour suppressor in some tissues and a tumour promoter in others. There is no clinical signal of new neoplasia in the trial record, but every Phase I/II study excluded subjects with a cancer history within 5 years, so the data simply does not exist for that population. Discontinue and seek workup for any unexplained lymphadenopathy, persistent night sweats, unexplained weight loss, or new mass during a cycle.
"SRT2104 was safe and well-tolerated over 28 days in elderly subjects at doses up to 2.0 g, with no evidence of serious adverse events or organ toxicity." — Libri V, Brown AP, Gambarota G, et al., PLoS One (2012).
Hard contraindications#
- Active malignancy or cancer history within the last 5 years. The dual role of SIRT1 in tumour biology and the trial exclusion criteria make this a firm line, not a soft caution.
- Pregnancy and lactation. No reproductive toxicology has been published; teratogenicity profile is unknown.
- Fasted administration. Not a safety contraindication but a protocol-breaking error — exposure is roughly a quarter of fed exposure. A fat-containing meal is non-negotiable.
- Mislabelled "SRT" powder from unverified vendors. SRT-1720 and SRT-2183 are related but distinct molecules with different selectivity profiles. COA / HPLC-MS verification is mandatory; without it, the compound in the capsule is unknown.
Gender, HPTA and PCT considerations#
SRT-2104 is non-hormonal. It does not bind androgen, estrogen, or progesterone receptors, does not aromatise, and does not suppress the HPTA. No PCT is required, and the compound is equally appropriate for male and female subjects — the GSK crossover PK study found no clinically meaningful sex differences, so the same dose tiers apply across the cohort. Pregnancy and lactation remain the one absolute exclusion on the female side, purely because reproductive toxicology was never completed before development was discontinued.
"SRT2104 is the most selective small-molecule SIRT1 activator developed so far, achieving allosteric activation, regulation of metabolic and inflammatory pathways, and improvement of multiple biomarkers in clinical studies." — Wu QJ, Zhang TN, Chen HH, et al., Scientific Reports (2024).
FAQ — SRT-2104
Research & citations
5 studies cited on this page.
Conclusion
SRT-2104 stands out as the most selective oral SIRT1 activator in the longevity toolkit, with strong lipid, anti-inflammatory, and mitochondrial biomarker support but minimal subjective effect profile.
Key takeaways:
- Standard dose: 500 mg once daily, strictly with a fat-containing meal for full bioavailability (Hoffmann 2013)
- Effective range: 250–2000 mg daily, depending on goal and study context; diminishing returns above 1 g
- Typical cycle: 4–12 weeks on, 4 weeks off; longevity protocols often pulse 5 days on / 2 off
- Stacking: pairs cleanly with NMN/NR for substrate support, metformin or rapamycin in multi-pathway longevity stacks
- Most robust clinical effects: LDL, total cholesterol, and triglyceride reduction alongside suppressed inflammatory cytokines (Venkatasubramanian 2013)
- Side effects are rare and mild, mainly GI discomfort at higher doses; no organ toxicity or hormonal suppression observed (Libri 2012)
For research into SIRT1-driven longevity and metabolic optimization, SRT-2104 offers a best-in-class oral framework — just respect the food-effect, verify purity, and design the protocol around biomarker improvements rather than acute performance changes.