Restoration of energy homeostasis by SIRT6 extends healthy lifespan

A. Roichman, S. Elhanati, M. A. Aon, I. Abramovich, A. Di Francesco, Y. Shahar, M. Y. Avivi, M. Shurgi, A. Rubinstein, Y. Wiesner, A. Shuchami, Z. Petrover, I. Lebenthal-Loinger, O. Yaron, A. Lyashkov, C. Ubaida-Mohien, Y. Kanfi, B. Lerrer, P. J. Fernández-Marcos, M. Serrano, E. Gottlieb, R. de Cabo and H. Y. Cohen ()
Additional contact information
A. Roichman: Bar-Ilan University
S. Elhanati: Bar-Ilan University
M. A. Aon: National Institute on Aging, NIH
I. Abramovich: Technion Integrated Cancer Center, Faculty of Medicine, Technion (Israel Institute of Technology)
A. Di Francesco: National Institute on Aging, NIH
Y. Shahar: Bar-Ilan University
M. Y. Avivi: Bar-Ilan University
M. Shurgi: Bar-Ilan University
A. Rubinstein: Bar-Ilan University
Y. Wiesner: Bar-Ilan University
A. Shuchami: Bar-Ilan University
Z. Petrover: Bar-Ilan University
I. Lebenthal-Loinger: Bar-Ilan University
O. Yaron: Bar-Ilan University
A. Lyashkov: National Institute on Aging, NIH
C. Ubaida-Mohien: National Institute on Aging, NIH
Y. Kanfi: Bar-Ilan University
B. Lerrer: Bar-Ilan University
P. J. Fernández-Marcos: Metabolic Syndrome Group–BIOPROMET, Madrid Institute for Advanced Studies-IMDEA Food, CEI UAM + CSIC
M. Serrano: Barcelona Institute of Science and Technology (BIST), Catalan Institution for Research and Advanced Studies (ICREA)
E. Gottlieb: Technion Integrated Cancer Center, Faculty of Medicine, Technion (Israel Institute of Technology)
R. de Cabo: National Institute on Aging, NIH
H. Y. Cohen: Bar-Ilan University

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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 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.

Date: 2021
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DOI: 10.1038/s41467-021-23545-7

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