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

Significance 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.

• Publication year

  2025

• Venue

  Proceedings of the National Academy of Sciences of the United States of America

• Publication date

  2025-11-11

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1073/pnas.2514084122PMID 41218122PMCID 12646208
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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