Researchers at Bar-Ilan University have discovered how the longevity-associated protein Sirt6 orchestrates a delicate molecular balancing act that protects the body from age-related decline and disease. The new findings, just published in the Proceedings of the National Academy of Sciences , reveal how Sirt6 preserves health during aging and may pave the way for therapies that promote a longer, healthier life.
Sirt6 is known for its powerful protective effects against age-related diseases such as cancer, diabetes, inflammation, and frailty. Its impact closely resembles that of calorie restriction, a dietary regimen proven in animals to extend lifespan and enhance the body’s natural repair and healing mechanisms.
Calorie restriction—eating fewer calories without malnutrition—has long been known to improve health and extend lifespan. One of its key effects is to increase the body’s production of hydrogen sulfide (H2S), a tiny gas molecule that supports wound healing, heart health, and brain function. This new study found that as we age, H2S levels naturally decline, weakening these protective benefits.
The study also revealed that Sirt6 mimics the effects of calorie restriction, keeping the body’s repair systems running smoothly by fine-tuning H2S production. However, unlike calorie restriction, which broadly raises H2S levels, Sirt6 does so with remarkable precision—boosting production when needed but also preventing dangerous overproduction.
Sirt6 prevents the age-related decline of H2S through the control of one-carbon metabolism
Aging is a major risk factor for multiple diseases, facing humanity with the challenge of how to prolong healthspan. Here, we explore a molecular mechanism underlying the prolongevity activity of the Sirt6 enzyme in supporting healthy aging. We show that Sirt6 maintains youthful hepatic levels of hydrogen sulfide (H2S), a gasotransmitter linked to the benefits of caloric restriction, by regulating cystine uptake and methionine metabolism. Sirt6 also prevents age-related increase in S-adenosylmethionine (SAM), the main methyl donor for epigenetic and protein methylation, through posttranslational acetylation. In addition, we define a link between one-carbon metabolism and the transsulfuration pathway. These findings reveal a mechanism of Sirt6 action and suggest potential therapeutic targets to support healthy aging.
Here is a structured analysis of the paper Sirt6 prevents the age‑related decline of H₂S through the control of one‑carbon metabolism (Touitou et al., Proc. Natl. Acad. Sci. 122(46):e2514084122, Nov 2025) (PubMed)
Executive summary
The authors investigate how the longevity-associated deacetylase enzyme SIRT6 sustains youthful levels of hydrogen sulfide (H₂S) in the liver during ageing, by modulating one-carbon / transsulfuration metabolism. They show that in aged wild-type mice, H₂S production in liver declines, whereas in mice overexpressing SIRT6 (“TG” model) H₂S production remains at youthful levels. They present mechanistic data: SIRT6 reduces expression of the cystine/glutamate antiporter subunit SLC7A11 via SP1, thereby decreasing cystine uptake and altering the transsulfuration flux; SIRT6 also deacetylates the enzyme MAT1A (lysine 235) thereby reducing S‐adenosylmethionine (SAM) overproduction, which limits activation of the enzyme CBS and thus constrains excessive H₂S production or methylation load. In sum, they propose that SIRT6 preserves homeostatic H₂S and SAM levels via post-translational and transcriptional regulation of key one-carbon/transsulfuration enzymes, and that this is a contributor to healthy ageing. The authors suggest this mechanism underlies part of SIRT6’s known pro-longevity effects.
Major novel contributions
Linking SIRT6 → one-carbon/transsulfuration → H₂S axis: While SIRT6 has been linked to longevity, chromatin regulation, metabolism and stress responses, this work identifies a previously un-described mechanistic axis: via SIRT6’s regulation of one-carbon metabolism (methionine/SAM cycle) and the transsulfuration pathway (that produces H₂S). This connection is new and significant for longevity research.
Decline of H₂S with aging and rescue via SIRT6: The finding that hepatic H₂S production declines with age in mice, and that this decline is prevented in SIRT6-overexpressing mice, is new. This reinforces the role of H₂S as a beneficial gasotransmitter in ageing and suggests mechanistic control.
MAT1A K235 deacetylation by SIRT6 as regulatory mechanism: They identify a specific acetylation site (K235) in MAT1A that is reduced in SIRT6 TG mice, show direct interaction between SIRT6 and MAT1A, and demonstrate in vitro that K235R (deacetylation mimic) reduces MAT1A activity. This establishes a concrete post-translational mechanism linking SIRT6 to SAM production control.
Dual regulatory mechanism (transcription + post-translational) to fine-tune flux: The model suggests SIRT6 acts on two fronts: decreasing cystine uptake (via SLC7A11) thereby influencing CGL/H₂S production, and reducing SAM production (via MAT1A deacetylation) thereby limiting CBS activation. The “gas pedal and brake” metaphor (from the press release) underscores this balanced regulatory logic. (EurekAlert!)
Proteomic/acetylomic dataset in aged liver: They provide a large dataset of ~6,349 acetylation sites in old mouse livers and show ~374 are SIRT6-dependent. This resource adds to the ageing/metabolism field.
Critique & limitations
While the study is elegant and contributes substantially, there are several points to note — both as caveats and opportunities for further research:
Strengths
The longitudinal ageing analysis (6-, 12-, 18-, 24-, 30-, 33-mo mice) provides a solid ageing context. (ResearchGate)
The multi-level mechanistic work (gene expression, proteomics, acetylomics, enzymatic assays, metabolomics) gives robust triangulation of the proposed pathway.
Use of SIRT6 TG mouse model gives in vivo relevance rather than only cell culture work.
Weaknesses / caveats
Overexpression model rather than loss-of-function or physiological modulation: The study uses SIRT6-overexpressing mice (TG). Overexpression may not reflect endogenous regulatory changes. It remains unclear whether modulation of SIRT6 within physiological ranges in ageing would replicate effect, and whether lowering SIRT6 in normal animals accelerates H₂S decline.
Tissue specificity: The authors show that the effect is liver‐specific (kidney/brain did not show same H₂S production rescue) (SI Appendix) (ResearchGate) — this raises question of how generalizable the mechanism is to other tissues relevant in ageing (heart, skeletal muscle, brain). For a systemic longevity mediator one might expect broader tissue action.
Causality to lifespan/healthspan: While the paper links SIRT6 to H₂S/SAM regulation and previous studies show SIRT6 overexpression extends lifespan, this work does not directly show that the H₂S/SAM axis is required for the longevity/healthspan benefits of SIRT6. For example, an experiment knocking down H₂S production in SIRT6 TG mice and observing lifespan/healthspan outcome would strengthen causality. Without that, the mechanistic link remains correlative (though strong).
Physiological relevance of H₂S levels and flux: While H₂S is increasingly recognized in ageing biology, the precise physiological range, tissue compartmentalization, and dose-response (beneficial vs toxic) remain open questions. The authors claim SIRT6 maintains H₂S “within its beneficial range” but don’t fully define what that range is, or test whether pushing H₂S higher improves outcomes or creates toxicity.
SAM/methylation consequences: The paper shows that SIRT6 TG mice maintain young-like SAM levels and methylation index. However, downstream epigenetic or methylation changes (gene expression, epigenetic marks) are not deeply explored. How much of the benefit is due to preventing methyl donor excess vs H₂S per se is left open.
Human relevance: While mention is made that a variant of SIRT6 is enriched in centenarians (in earlier work) (ResearchGate), this study is fully in mouse/hepatic models and cell culture. Translating this to human ageing or therapeutic target remains distant.
Complexity and redundancy in metabolism: One-carbon and transsulfuration metabolism are highly interconnected, redundant, and compensated. The study focuses on MAT1A, CBS, CGL, SLC7A11, but other enzymes and fluxes might modulate H₂S and SAM independently. The authors themselves note that many other acetylated enzymes in the dataset may also contribute. (ResearchGate)
Quantitative flux vs static measurement: The study mostly measures enzyme activity, steady state metabolite levels (H₂S production capacity, SAM/SAH), acetylation states, and gene/protein expression. Comprehensive flux analysis (e.g., tracing labelled methionine/cysteine to H₂S, SAM, glutathione) would strengthen quantitative understanding of dynamics.
Ageing confounders: The aged mice (23-25 mo etc) likely have multiple metabolic, hormonal, inflammatory changes that could influence H₂S, one-carbon metabolism, and SIRT6 expression/function. While SIRT6 TG appears to rescue some of these, teasing apart direct vs indirect effects is challenging.
Implications for longevity/healthspan research
This work underscores that longevity regulators (here SIRT6) may exert part of their effect by fine-tuning metabolic fluxes (specifically one-carbon and transsulfuration) rather than just activating generic stress responses.
H₂S emerges again as a candidate beneficial gasotransmitter in ageing, but importantly the study suggests it’s not simply more is better — regulation (and avoiding overshoot) appears critical.
SAM/methyl donor regulation may matter more in ageing than is often appreciated: preventing excess methylation capacity (or methylation stress) might contribute to healthy ageing.
Potential therapeutic targets: manipulating SLC7A11 (cystine uptake), MAT1A acetylation, or H₂S production (via CBS/CGL) might have translational relevance—but safety, tissue selectivity, and flux balancing will be crucial.
Summary verdict
This is a strong and novel piece of work that advances our mechanistic understanding of how SIRT6 may promote healthy ageing by linking it to one-carbon and transsulfuration metabolism, especially via H₂S and SAM regulation. It opens interesting therapeutic angles for longevity science. However, it remains primarily mechanistic, in an over-expression model, in one tissue (liver), and does not yet definitively prove that the H₂S/SAM axis is the causal mediator of SIRT6’s pro-longevity effects. For your focus (biotech, longevity, health-span optimisation) the paper is highly relevant and suggests avenues worth exploring (e.g., modulators of SLC7A11, MAT1A acetylation, H₂S donors/regulators). But translation to humans and safe therapeutic manipulation remains a substantial leap.
If you like, I can pull out the key figures, produce a tabular breakdown of the experiments (design, result, limitations) or generate an actionable insight list (for longevity/Biotech R&D).
Here’s a summary of what the current scientific literature says about interventions that might boost SIRT6 in humans — and a reality-check on the gap between hope and evidence.
What we do know
SIRT6 is a NAD⁺-dependent deacylase/ADP-ribosyltransferase, involved in DNA repair, metabolic regulation, chromatin homeostasis and ageing. (PMC)
Several small-molecule activators of SIRT6 have been identified in preclinical studies (cells, animals). For example: UBCS039, MDL‑811, etc. (Theranostics)
A biotech company SirTLab Corporation is preparing human trials of therapies that aim to activate SIRT6. (NAD.com)
Reviews explicitly state that while SIRT6 is a promising target, modulators “remain at the chemical probe stage” and few compounds have progressed to human use. (PMC)
What we don’t have (yet)
There is no robust, peer-reviewed clinical trial showing that a supplement or drug reliably increases SIRT6 levels or activity in humans and yields improved health/longevity outcomes.
The preclinical activators are mostly in vitro/cell/animal model stage. For example, MDL-811 has shown “in vivo” efficacy in cancer models but not yet in ageing/human healthspan contexts. (Theranostics)
Even if a compound increases SIRT6 expression or activity, the downstream effects (safety, off-target, tissue specificity, context dependence) are not well characterised in humans.
SIRT6 has complex, even dual roles in cancer (tumour suppressor or promoter depending on context) so indiscriminate activation may carry risk. (MDPI)
Practical takeaway for your biotech/longevity lens
Given your focus on longevity/healthspan optimisation, here are actionable points:
Monitor the human trials of SIRT6 activators (e.g., SirTLab’s work). If successful, they may become first-in-class for this target.
For now, any “supplement that boosts SIRT6” is speculative. If you consider product/marketing development, you would need to be explicit about the uncertainty.
Consider indirect approaches: since SIRT6 is NAD⁺-dependent, interventions that boost NAD⁺ (e.g., NR, NMN) might indirectly support SIRT6 activity (but that’s not the same as up-regulating SIRT6 expression or specifically activating it).
Also consider lifestyle/metabolic interventions known to up-regulate sirtuins in broad (though not SIRT6-specific) ways: caloric restriction, exercise, metabolic stressors — these may support the sirtuin network.
If developing a supplement product, you’d need to navigate regulatory/claims environment carefully — you cannot claim “SIRT6 activation proven in humans” today.
What we do know
What we don’t have (yet)
Practical takeaway for your biotech/longevity lens