SIRT6 Promotes Healthy Longevity by Rewiring the Old Metabolome

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 and increased physical activity. To explore the mechanisms underlying SIRT6 positive effects on healthy longevity and the SIRT6 dependent metabolome, transcriptome and acetylome were characterized in WT and SIRT1 or SIRT6 Tg mice. Together, 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. SIRT6 overexpression reduces IGF-1 levels and signaling, represses inflammation response and induces liver and muscle AMPK activity. In addition, by controlling the acetylation status of multiple enzymes, it reprograms various key metabolic tissues to provide the required energy when nutrients are limited such as in aged animal. These findings suggest a new mechanism for the regulation of healthy longevity by SIRT6.