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.
Bibliographical noteFunding Information:
We thank the members of the Cohen lab for their helpful comments on the manuscript. This study was supported by the Israel Science Foundation (621/13 and 777/16), I-Core Foundation (41/11), ESFD, D-Cure, Israel Cancer Association (2016-0103), ICRF and BSF, and the SAGOL center of healthy human aging. A. Roichman is supported by the Adams Fellowship Program of the Israel Academy of Sciences and Humanities. R.d.C., M.A.A., and C.U.M. are supported by the Intramural Research Program of the National Institute on Aging, NIH. E.G. is supported by the I-Core foundation (1775/12) and Laura and Isaac Perlmutter Foundation. Work in the laboratory of M. Serrano was funded by the IRB and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund (ERDF) (SAF2017-82613-R), the European Research Council (ERC-2014-AdG/669622) and “La Caixa” Foundation.
© 2021, The Author(s).