SIRT6 enhances lifespan and healthspan in mice by activating fasting metabolism

Sirtuins are NAD⁺-dependent protein deacylases and/or mono ADP ribosyltransferases. There are seven mammalian Sirtuin members (termed SIRT1-7) which have roles in several cellular processes including DNA repair, metabolism and cancer. SIRT6 was shown by our lab to regulate lifespan of male, but not female mice. However, whether this effect is reproducible in other mouse strains, whether SIRT1 is involved in this mechanism, and which metabolic pathways are involved in SIRT6 lifespan extension remain elusive. Here, we tracked the lifespan of C57BL/6J mice overexpressing either SIRT1, SIRT6 or SIRT1+6, and found a significant SIRT6-dependent increase in lifespan of both male and female mice. Old SIRT6-transgenic (SIRT6-tg) mice were protected from age related decline in body weight and age related anemia, had increased HDL levels and lower LDL levels. Additionally, they displayed increased physical activity and had less gastrointestinal adenomas, indicating that SIRT6 overexpression improves various healthspan parameters in mice. We characterized the homeostasis of glucose in young mice, comprising molecular and biochemical signatures, and its deterioration during aging. Strikingly, this crucial metabolic balance was completely preserved in old SIRT6-tg, but not SIRT1-tg mice. SIRT6 induced a catabolic state, resembling fasting and caloric restriction. By performing serum metabolomics in response to fed-fast transition together with liver RNA-seq, proteomics, metabolomics and in vivo stable isotope tracing we found a strong evidence that key metabolic pathways decreased during aging are activated in SIRT6-tg mice. Collectively, these results suggest that improved glucose homeostasis and energetics in SIRT6-tg mice are key parameters affecting healthspan and lifespan.