Sirt6 prevents the age-related decline of H <sub>2</sub> S through the control of one-carbon metabolism
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 2 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 2 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 2 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 2 S production. The net outcome is H 2 S and SAM levels as observed in young animals. Thus, we unveil a fundamental mechanism for the promotion of healthy longevity by Sirt6.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (24)
Noga Touitou
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University
Liat Nahum
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University
Sarit Feldman-Trabelsi
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University
Matan Y. Avivi
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University
Miguel A. Aon
Translational Gerontology Branch and Laboratory of Cardiovascular Sciences, National Institute on Aging, NIH
Shoshana Naiman
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University
Moran Rathaus
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University
Asaf A. Gertler
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University
Asael Roichman
Lia Berkman Dvir
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University
Michel Bernier
Translational Gerontology Branch and Laboratory of Cardiovascular Sciences, National Institute on Aging, NIH
Nirad Banskota
Translational Gerontology Branch and Laboratory of Cardiovascular Sciences, National Institute on Aging, NIH
Lir Beck
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University
Ron Nagar
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University
Zacharia Schwartz
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University
Nathan L. Price
Translational Gerontology Branch, National Institute on Aging
Michal Harel
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University
Batia Lerrer
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University
Isao Ishii
Department of Health Chemistry, Showa Pharmaceutical University
Hanoch Senderowitz
Department of Chemistry, Bar-Ilan University
Ruin Moaddel
Translational Gerontology Branch and Laboratory of Cardiovascular Sciences, National Institute on Aging, NIH
Tamar Geiger
Rafael de Cabo
Translational Gerontology Branch and Laboratory of Cardiovascular Sciences, National Institute on Aging, NIH
Haim Y. Cohen
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University