A new study (Touitou et al., PNAS, 2025) identifies a precise molecular mechanism whereby the longevity-associated enzyme SIRT6 preserves youthful levels of the gasotransmitter Hydrogen sulfide (H₂S) in liver — by reprogramming one-carbon and transsulfuration metabolism.
Mechanistic insight
As mice age, their hepatic H₂S production capacity declines while the methyl donor S-adenosylmethionine (SAM) accumulates. Overexpression of SIRT6 reverses both effects: old SIRT6 transgenic mice maintain liver H₂S production similar to young mice, and avoid the age-associated rise in SAM. Mechanistically, SIRT6 downregulates the cystine importer SLC7A11 (xCT) via suppression of the transcription factor Sp1, reducing cystine uptake and shifting metabolism toward increased H₂S generation through the enzyme Cystathionine γ‑lyase (CGL). Concurrently, SIRT6 deacetylates key one-carbon enzymes, notably Matα1 at lysine-235, which reduces its SAM-synthesizing activity and limits downstream activation of Cystathionine β‑synthase (CBS). The net effect restores a youthful balance between methylation potential and H₂S generation.
This represents a mechanistically novel link between sirtuin biology, one-carbon metabolism, and H₂S — positioning SIRT6 not simply as a “longevity gene,” but as a metabolic rheostat calibrating methylation and H₂S-mediated signalling.
Why this matters (novelty + longevity relevance)
- Prior work associated H₂S with benefits of calorie-restriction (CR). This is the first demonstration that SIRT6 regulates H₂S homeostasis endogenously, via one-carbon metabolism remodeling.
- It sheds light on how CR-induced elevation in H₂S might be physiologically downstream of sirtuin activation, not just a byproduct of nutrient stress.
- By restraining age-associated SAM build-up, SIRT6 may also modulate epigenetic drift, methylation imbalance, and protein methylation stress — all factors implicated in aging.
Actionable insights for a longevity-oriented biohacker
| Hypothesis / Intervention | What to Monitor / Measure | Potential Protocol Ideas |
|---|---|---|
| Upregulate SIRT6 (via e.g. SIRT6-activators, NAD⁺ precursors, mild CR) | Plasma/circulating H₂S (or stable metabolites like thiosulfate), SAM/SAH ratio, global methylation markers (e.g. 5-mC), cystathionine levels, IGF-1 | Cycle mild CR or fasting-mimicking diet with NAD⁺ boosting (nicotinamide riboside / NMN), monitor H₂S and methylation monthly; adjust to avoid excessive SAM suppression |
| Exogenous H₂S donor supplementation (e.g. GYY4137, sodium thiosulfate) + methylation-balance support (e.g. B-vitamins, choline) | As above + liver/kidney function, vascular reactivity, endothelial markers, inflammation (CRP, IL-6) | Low-dose donor twice weekly, co-supplement with methyl acceptors to buffer methylation demands; measure before/after 6–12 weeks |
| Methionine / cystine intake modulation (dietary restriction of methionine, cystine) | SAM/SAH ratio, homocysteine, glutathione, H₂S metabolites, redox markers | Use methionine-reduced diet, track biochemical adaptation and redox status over 3–6 months |
Cost-effectiveness: compared to expensive “clean-senolytics” or novel small molecules, dietary modulation (methionine restriction or mild CR) plus NAD⁺ precursors yields potentially high “bang for buck”: inexpensive, low-risk, and mechanistically anchored. Exogenous H₂S donors remain cost-moderate but carry less- certain long-term safety and dose-optimization uncertainty.
Critical limitations and questions
- Translational uncertainty: all data are from mice; liver-specific effects may not reflect systemic H₂S dynamics in humans, especially across organs (brain, vasculature). The study reports no effect in kidney or brain.
- Effect-size and functional significance: The paper demonstrates restoration of H₂S production and SAM balance biochemically, but does not link directly to lifespan extension or organ-specific functional endpoints (frailty, vascular health, cognition).
- Dose-response and safety: Overproduction of H₂S can be toxic; the study shows SIRT6 acts as a brake to avoid dangerous excess, but exogenous modulation may not afford such tight regulation.
- Methodological caution: Proteomic and acetylome changes are associative; causal links (e.g. between Matα1 deacetylation and systemic longevity) remain speculative until validated in rigorous lifespan / functional studies.
Further data needed: long-term studies assessing whether SIRT6-driven H₂S preservation actually translates into improved organ health, extended healthspan, and lifespan — ideally in higher mammals or human observational cohorts; measurement of tissue-specific H₂S, methylation and autophagy / repair markers; and safety profiles for H₂S donor or SIRT6-activating interventions in humans.
Conclusion: this paper provides a strong mechanistic argument for SIRT6 as a central regulator of one-carbon and transsulfuration metabolism, preserving youthful H₂S and methylation balance. For a longevity-oriented biohacker, it frames a plausible, cost-effective axis for intervention — but careful biomarker-driven experimentation, dose titration, and rigorous monitoring are essential before extrapolating to human healthspan strategies.
Key questions a longevity-oriented biohacker may want to ask
- In humans, does hepatic SIRT6 expression decline with age in a way that correlates with reduced systemic (or organ-specific) H₂S or altered SAM/SAH ratios?
- Are circulating H₂S (or stable metabolites like thiosulfate) and SAM/SAH reliable surrogate biomarkers for tissue-specific activity (e.g. liver, vascular endothelium, brain)?
- Could moderate CR or fasting-mimicking diets upregulate SIRT6 sufficiently to restore youthful H₂S/SAM balance without triggering adverse effects (e.g. nutrient deficiency)?
- Would chronic use of H₂S donors (e.g. slow-release compounds) recapitulate benefits seen with SIRT6 overexpression — or disrupt homeostatic control, risking toxicity or dysregulated methylation?
- How does preserved H₂S production via SIRT6 influence downstream longevity pathways (e.g. autophagy, mitochondrial function, vascular health, inflammatory signalling, epigenetic drift)?
- Does SIRT6-mediated methylation control (via SAM suppression) impact epigenetic age markers (e.g. methylation clocks), and could that translate into slowed biological aging?
- What is the optimal dose/timing regimen for NAD⁺ precursors or other SIRT6-activating interventions to maximize H₂S/SAM benefits while minimizing risks?
- Could combining methionine/cystine-restricted diet with NAD⁺ precursors and periodic H₂S donors create a synergistic “stack” — and would such a stack be more cost-effective and safer than other interventions (e.g. rapamycin, senolytics)?
- Does preserved H₂S production support vascular and cognitive function in aging — and if so, which biomarkers (e.g. flow-mediated dilation, endothelial markers, neurocognitive testing) should be tracked in n=1 experiments?
- How stable and reproducible are the biochemical effects (H₂S, SAM, methylation status) over time in adults — and what is the intra-individual variability?