Maintaining healthy longevity by SIRT6

Sirtuins are NAD+ dependent deacylases, homologues of the yeast SIR2 protein that were shown to play a major role in regulating lifespan and healthspan. Mice over expressing SIRT6, one of the seven mammalian sirtuins, have extended lifespan along with significant improvement of their healthspan. In comparison to their wild-type (WT) littermates, old SIRT6 transgenic (Tg) mice showed amelioration of a variety of age-related disorders, including: improved glucose tolerance, younger hormonal profile, reduced age-related adipose inflammation, increased physical activity and reduced frailty. To explore the mechanisms underlying SIRT6 positive effects on healthy longevity the SIRT6ome, i.e. the SIRT6 dependent metabolome and acetylome were characterized in WT and SIRT6 Tg mice. These analyses demonstrated that SIRT6 overexpression rewired the metabolism of the old animal to a young-liked signaling network. SIRT6 overexpression mimics key features of the metabolic profile of dietary restriction (DR), a well-known treatment that extends healthy lifespan in multiple organisms. In addition, this phenotype was accompanied with increased free fatty acids b-oxidation and muscle AMP-activated protein kinase (AMPK) activity and mTOR inhibition. At the acetylome level, we identified that SIRT6 control the acetylation level of vast majority of the enzymes of the transsulfuration (TSP)/one carbon pathway and promotes its positive effect on longevity. Altogether, these changes provide the required energy when nutrients are limited such as in aged animal and suggest a new mechanism for the regulation of healthy longevity by SIRT6.