Sirt6 prevents the age-related decline of H <sub>2</sub> S through the control of one-carbon metabolism

Mice overexpressing Sirt6 or fed a caloric restriction (CR) diet live longer with improved health. CR increases Sirt6 levels, and its beneficial effects are mediated by the gasotransmitter H<sub>2</sub>S, a one-carbon pathway product. Yet, the role of this pathway in Sirt6-regulated longevity remains elusive. Here, we show that Sirt6 controls hepatic one-carbon metabolism, preventing the aging-dependent H<sub>2</sub>S reduction, and the elevation of the methyl donor, S-adenosylmethionine (SAM). Sirt6 downregulates Slc7a11 expression in an Sp1-dependent manner, decreasing cystine uptake and increasing Cgl H<sub>2</sub>S production activity. Additionally, comparative acetylome in old livers revealed Sirt6-related differential acetylation of most of the one-carbon enzymes. Specifically, Sirt6-dependent Matα1 K235 deacetylation reduces its SAM production activity and Cbs binding, thereby reducing its activation of Cbs-dependent H<sub>2</sub>S production. The net outcome is H<sub>2</sub>S and SAM levels as observed in young animals. Thus, we unveil a fundamental mechanism for the promotion of healthy longevity by Sirt6.

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Journal
Proceedings of the National Academy of Sciences
Published
2025-11-11
DOI
https://doi.org/10.1073/pnas.2514084122
Primary Topic
Sirtuins and Resveratrol in Medicine
Type
article
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article

Sirt6 prevents the age-related decline of H 2 S through the control of one-carbon metabolism

M. Rathaus, Isao Ishii, Hanoch Senderowitz, Ruin Moaddel et al.
Proceedings of the National Academy of Sciences
Sirtuins and Resveratrol in Medicine
article

Sirt6 prevents the age-related decline of H 2 S through the control of one-carbon metabolism

M. Rathaus, Isao Ishii, Hanoch Senderowitz, Ruin Moaddel, Matan Y. Avivi, Tamar Geiger, Lir Beck, Miguel A. Aon, Asael Roichman, Haim Cohen, Michal Harel, Rafael de Cabo, Asaf A. Gertler, Nirad Banskota, Shoshana Naiman, Noga Touitou, R. Nagar, Michel Bernier, Zvi Schwartz, Liat Nahum, Nathan L. Price, Batia Lerrer, Sarit Feldman-Trabelsi, Lia Berkman Dvir
article en

Abstract

Mice overexpressing Sirt6 or fed a caloric restriction (CR) diet live longer with improved health. CR increases Sirt6 levels, and its beneficial effects are mediated by the gasotransmitter H<sub>2</sub>S, a one-carbon pathway product. Yet, the role of this pathway in Sirt6-regulated longevity remains elusive. Here, we show that Sirt6 controls hepatic one-carbon metabolism, preventing the aging-dependent H<sub>2</sub>S reduction, and the elevation of the methyl donor, S-adenosylmethionine (SAM). Sirt6 downregulates Slc7a11 expression in an Sp1-dependent manner, decreasing cystine uptake and increasing Cgl H<sub>2</sub>S production activity. Additionally, comparative acetylome in old livers revealed Sirt6-related differential acetylation of most of the one-carbon enzymes. Specifically, Sirt6-dependent Matα1 K235 deacetylation reduces its SAM production activity and Cbs binding, thereby reducing its activation of Cbs-dependent H<sub>2</sub>S production. The net outcome is H<sub>2</sub>S and SAM levels as observed in young animals. Thus, we unveil a fundamental mechanism for the promotion of healthy longevity by Sirt6.

Proceedings of the National Academy of SciencesVol. 122(46)
Bar-Ilan University (IL), Tel Aviv University (IL), Goodman (Japan) (JP), Human Longevity (United States) (US), National Institute on Aging (US), Showa Pharmaceutical University (JP)
Openalex Percentile: Top 59%
Sirtuins and Resveratrol in Medicine
DOISourceOpenAlex
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