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Restoration of energy homeostasis by SIRT6 extends healthy lifespan

Roichman, A., Elhanati, S., Aon, M. A., Abramovich, I., Di Francesco, A., Shahar, Y., Avivi, M. Y., Shurgi, M., Rubinstein, A., Wiesner, Y., Shuchami, A., Petrover, Z., Lebenthal-Loinger, I., Yaron, O., Lyashkov, A., Ubaida-Mohien, C., Kanfi, Y., Lerrer, B., Fernández-Marcos, P. J., Serrano, M., Gottlieb, E., de Cabo, R., Cohen, H. Y.·2021·Nature Communications
DOI 10.1038/s41467-021-23545-7PMC PMC8163764
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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 13 C 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.

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Metadata

Authors
Roichman, A., Elhanati, S., Aon, M. A., Abramovich, I., Di Francesco, A., Shahar, Y., Avivi, M. Y., Shurgi, M., Rubinstein, A., Wiesner, Y., Shuchami, A., Petrover, Z., Lebenthal-Loinger, I., Yaron, O., Lyashkov, A., Ubaida-Mohien, C., Kanfi, Y., Lerrer, B., Fernández-Marcos, P. J., Serrano, M., Gottlieb, E., de Cabo, R., & Cohen, H. Y.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-05-28
Volume
12
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-021-23545-7
PMC
PMC8163764
Cited by
214
References
20
Language
en
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