Sirtuins are a family of proteins that largely undertake specific modification of other proteins, removing certain decorations that have been attached to those proteins. A great deal of the exceedingly complex regulation of cellular metabolism involves changing the function of molecules by adding or removing decorations such as acetyl groups, methyl groups, and so forth. Several sirtuins have been investigated in the context of aging, showing some ability to alter the operation of cellular metabolism to modestly slow aspects of aging in animal models. Sirtuin 1 was excessively overhyped and is probably not in actual fact very relevant to aging, but sirtuin 6 has the appearance of being more reliable in its effects, albeit still not large effects in the grand scheme of things.
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).
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 H2S, 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 H2S 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 cystathionine gamma lyase (Cgl) H2S production activity. Additionally, comparative acetylome in old livers revealed Sirt6-related differential acetylation of most of the one-carbon enzymes. Specifically, Sirt6-dependent Matα1 deacetylation reduces its SAM production activity and cystathionine beta synthase (Cbs) binding, thereby reducing its activation of Cbs-dependent H2S production. The net outcome is H2S and SAM levels as observed in young animals. Thus, we unveil a fundamental mechanism for the promotion of healthy longevity by Sirt6.
Link: https://doi.org/10.1073/pnas.2514084122
View the full article at FightAging
