Tier 3 — preclinical

Sirt6 prevents the age-related decline of H2S through the control of one-carbon metabolism

Touitou N, Nahum L, Feldman-Trabelsi S, Avivi MY, Aon MA, Naiman S, Rathaus M, Gertler AA, Roichman A, Berkman Dvir L, Bernier M, Banskota N, Beck L, Nagar R, Schwartz Z, Price NL, Harel M, Lerrer B, Ishii I, Senderowitz H, Moaddel R, Geiger T, de Cabo R, Cohen HY

Proceedings of the National Academy of Sciences of the United States of America 2025 Volume 122, issue 46, article e2514084122

Bibliography

DOI: 10.1073/pnas.2514084122
PubMed: PMID 41218122
PubMed Central: PMC12646208
Funding: Israel Science Foundation (777/16 and 890/21), US-Israel Binational Science Foundation (2019312, 2023151), Israel Cancer Research Fund, Samuel Waxman Cancer Research Foundation, MINERVA (AZ5746940769), Israeli Ministry of Innovation, Science and Technology, Sagol center of healthy human aging. Research supported in part by the Intramural Research Program at the NIA, NIH.
Competing interests: H.Y.C. advices SirtLab. The other authors declare no conflicts of interest.

Study snapshot

Design	Interventional preclinical study — comparison of aged (23–25 mo) Sirt6-transgenic (Sirt6 TG, "MOSES") mice vs. wild-type C57BL/6JOlaHsd littermates. Supplemented with HEK293T SIRT6-knockout cell studies and label-free LC-MS/MS acetylome + proteome analysis.
Model	Sirt6-transgenic mice (whole-body overexpression), aged wild-type C57BL/6 controls; SIRT6-knockout HEK293T cells; recombinant Matα1, Cbs and Cgl protein assays; mouse primary hepatocyte cultures.
Sample	n=6–14 per group across assays; n=9 per genotype for the acetylome; n=3–5 across cell-culture replicates.
Intervention	Whole-body Sirt6 overexpression from birth (transgenic); SIRT6 reintroduction in knockout HEK293T cells; site-directed mutagenesis of Matα1 K235 (K235Q acetyl-mimic, K235R deacetyl-mimic) and Cbs D440N (SAM-insensitive) mutants; DL-propargylglycine (PAG) Cgl inhibitor injection.
Duration	Longitudinal comparison at 3 mo (young) and 23–25 mo (old); acute PAG injection for IGF-1 measurement.
Endpoints	Hepatic H2S production capacity; Slc7a11 mRNA and protein expression; Sp1 protein levels; Matα1 K235 acetylation status; SAM and SAH liver concentrations; SAM/SAH methylation index; Cbs and Cgl activity; Serum IGF-1 levels; Global liver acetylome (6,349 sites on 1,722 proteins)

What the study showed, in plain terms

This is a mouse mechanism paper from the same Israeli research group that first showed SIRT6 extends lifespan in male mice (Kanfi 2012). It answers a specific question — how does SIRT6 actually deliver its longevity benefit at the molecular level in aged tissue?

The team compared aged (roughly 70-human-year equivalent) SIRT6-overexpressing mice to aged normal mice. In the aged normal livers, production of hydrogen sulfide — a small gas molecule that supports healthspan and rises with caloric restriction — had dropped. In the aged SIRT6-overexpressing livers, hydrogen sulfide production was back at youthful levels. The methyl donor SAM, which drives DNA and protein methylation and rises abnormally with age, was also kept in check.

The mechanism has two arms. First, SIRT6 suppresses the transcription factor Sp1, which shuts down the Slc7a11 cystine transporter and boosts a downstream H2S-producing enzyme. Second, SIRT6 directly deacetylates a specific site (K235) on the SAM-producing enzyme Matα1, which throttles SAM overproduction and prevents excess activation of the transsulfuration pathway. Together these two arms rebalance one-carbon metabolism to a "young" state.

The authors position SIRT6 activation as a way to obtain the metabolic benefits of caloric restriction without the dietary restriction — a mechanistic thesis, not a clinical claim.

Key findings

Aged wild-type mouse livers show a significant drop in hydrogen sulfide (H2S) production capacity compared to young mice. Aged SIRT6-transgenic mice maintain youthful H2S levels — approximately twofold higher than aged wild-type controls, without any change in the H2S-producing enzymes Cbs or Cgl.
The mechanism is liver-specific. SIRT6 overexpression did not raise H2S production in kidney or brain, indicating the pathway is tissue-selective.
SIRT6 downregulates the cystine/glutamate antiporter Slc7a11 (xCT) at the mRNA level via reduction of the transcription factor Sp1. This is independent of SIRT6's deacetylase activity — a catalytically dead SIRT6 mutant (H133Y) suppresses Slc7a11 just as effectively.
SIRT6 directly deacetylates Matα1 at lysine 235 (K235). The K235R deacetyl-mimic mutant has significantly reduced intrinsic SAM-producing activity and reduced binding to Cbs, throttling the transsulfuration pathway.
SAM levels rise with age in normal mouse liver but stay young-like in SIRT6-transgenic aged mice. The SAM/SAH methylation index is significantly higher in aged wild-type mice, and significantly restored to young-like levels in aged SIRT6-transgenic mice.
Comparative liver acetylome across 6,349 lysine sites on 1,722 proteins found SIRT6-dependent differential acetylation on most enzymes of the one-carbon metabolism pathway, including Cbs, Matα1, Gnmt, Shmt2, and Dmgdh.
Pharmacological inhibition of Cgl with DL-propargylglycine (PAG) reverses the SIRT6-driven reduction in serum IGF-1, confirming that H2S production is a mediator of SIRT6's healthspan phenotype.

What this study can and cannot tell us

This is a preclinical mechanism study in mice. All findings need human replication before they can inform supplementation strategy. The Sirt6-transgenic mouse used here (Sirt6 TG / "MOSES") overexpresses SIRT6 from birth — this is not equivalent to raising SIRT6 activity in a middle-aged adult via a supplement or small-molecule activator. Whether starting SIRT6 activation later in life reproduces the H2S and SAM rescue is explicitly acknowledged as unanswered.

The mechanism is described in liver only. Kidney and brain showed no H2S rescue on the same intervention. The one-carbon metabolism story is therefore hepatic, not systemic — implications for cognitive ageing, muscle ageing, or cardiovascular ageing are not addressed by this paper.

The corresponding author advises SirtLab, a Bar-Ilan-affiliated biotechnology company developing SIRT6 activators. The finding — that SIRT6 activation phenocopies caloric restriction — aligns commercially with the company's positioning. This is disclosed clearly in the competing interests statement; the mechanistic data itself is well controlled and consistent with the wider literature from independent labs, but reader awareness of the commercial context is appropriate.

The Sp1 suppression arm is independent of SIRT6's deacetylase activity, meaning a small-molecule activator that only enhances SIRT6's catalytic activity would recover the Matα1/SAM arm but potentially not the Slc7a11/H2S arm. This has direct implications for interpreting activator development but is not fully unpacked in the paper.

Tier 3

The sirtuin SIRT6 regulates lifespan in male mice

Kanfi Y et al. · Nature · 2012