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Restoration of energy homeostasis by SIRT6 extends healthy lifespan

ABSTRACT: Aging leads to a gradual decline in physical activity and disrupted energy homeostasis. The NAD+-dependent SIRT6 deacylase regulates aging and metabolism through mechanisms that largely remain unknown. Here, we show that SIRT6 overexpression leads to a reduction in frailty and lifespan extension in both male and female B6 mice. A combination of physiological assays, in vivo multi-omics analyses and 13C lactate tracing identified an age-dependent decline in glucose homeostasis and hepatic gluconeogenesis (GNG) capacity in wild type mice. In contrast, aged SIRT6-transgenic mice preserve GNG capacity and glucose homeostasis through an improvement in the utilization of two major GNG precursors, lactate and glycerol. To mediate these changes, mechanistically, SIRT6 increases hepatic GNG gene expression, de novo NAD+ synthesis, and systemically enhances glycerol release from adipose tissue. These findings show that SIRT6 optimizes energy homeostasis in old age to delay frailty and preserve healthy aging.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Ceereena Ubaida-Mohien

LAB HEAD: Haim Y. Cohen

PROVIDER: PXD021447 | Pride | 2021-03-11

REPOSITORIES: Pride

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