Restoration of energy homeostasis by SIRT6 extends healthy lifespan
Nature Communications volume 12, Article number: 3208 (2021 ) Cite this article
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 glucose output in wild type mice. In contrast, aged SIRT6-transgenic mice preserve hepatic glucose output and glucose homeostasis through an improvement in the utilization of two major gluconeogenic precursors, lactate and glycerol. To mediate these changes, mechanistically, SIRT6 increases hepatic gluconeogenic 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.
Aging is associated with an overall decline in health, increased frailty and is a major risk factor for multiple chronic diseases1. Therefore, increasing our understanding of the mechanisms underlying aging processes is a top priority to enable the development of interventions that will lead to the preservation of health and improvements on survival/lifespan.
