A Small Step for A Protein, A Great Leap for The Pathway: Sirt6-dependent Regulation of Methionine and Cysteine Metabolism

Sirt6 is a well-established regulator of healthspan and lifespan. Nevertheless, though extensively researched, the exact mechanism of Sirt6-mediated longevity is not fully understood. To gain a better view on the impact of Sirt6 in the cell, a comparative acetylome was done in old WT mice versus Sirt6 overexpressing transgenic mice. Among multiple metabolic processes, we found widespread changes in the acetylation status of one carbon metabolism, an essential factor in the beneficial effects of caloric restriction diet. Under normal conditions, the metabolic flow of this pathway is carefully balanced since great changes in its activity may lead to sever pathophysiologies. Given that protein acetylation is a small modification that occurs in low percentages, it is an optimal way to tune the metabolic flow for its beneficial physiological effects. Through this, we have found a new mechanism in which Sirt6 regulates healthy lifespan.