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; H. Y. Cohen

doi:10.1038/s41467-021-23545-7

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. SerranoE. Gottlieb, R. de Cabo, H. Y. Cohen

The Mina and Everard Goodman Faculty of Life Sciences

Research output: Contribution to journal › Article › peer-review

112 Scopus citations

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.

Original language	English
Article number	3208
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-23545-7
State	Published - 28 May 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

Funding

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.

Funders	Funder number
D-Cure
ESFD
I-Core Foundation	41/11
Laura and Isaac Perlmutter Foundation
National Institutes of Health	1775/12
National Institute on Aging	ZIAAG000362
Israel Cancer Research Fund
European Commission	ERC-2014-AdG/669622
United States-Israel Binational Science Foundation
Israel Academy of Sciences and Humanities
Israel Cancer Association	2016-0103
Israel Science Foundation	621/13, 777/16
European Regional Development Fund	SAF2017-82613-R
Ministerio de Economía, Industria y Competitividad, Gobierno de España

Access to Document

10.1038/s41467-021-23545-7

Cite this

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., ... Cohen, H. Y. (2021). Restoration of energy homeostasis by SIRT6 extends healthy lifespan. Nature Communications, 12(1), Article 3208. https://doi.org/10.1038/s41467-021-23545-7

@article{f3389c5d5a73445892c88fcdbce2b8f6,

title = "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 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.",

author = "A. Roichman and S. Elhanati and Aon, {M. A.} and I. Abramovich and {Di Francesco}, A. and Y. Shahar and Avivi, {M. Y.} and M. Shurgi and A. Rubinstein and Y. Wiesner and A. Shuchami and Z. Petrover and I. Lebenthal-Loinger and O. Yaron and A. Lyashkov and C. Ubaida-Mohien and Y. Kanfi and B. Lerrer and Fern{\'a}ndez-Marcos, {P. J.} and M. Serrano and E. Gottlieb and {de Cabo}, R. and Cohen, {H. Y.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = may,

day = "28",

doi = "10.1038/s41467-021-23545-7",

language = "אנגלית",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Roichman, A, Elhanati, S, Aon, MA, Abramovich, I, Di Francesco, A, Shahar, Y, Avivi, MY, 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, PJ, Serrano, M, Gottlieb, E, de Cabo, R & Cohen, HY 2021, 'Restoration of energy homeostasis by SIRT6 extends healthy lifespan', Nature Communications, vol. 12, no. 1, 3208. https://doi.org/10.1038/s41467-021-23545-7

TY - JOUR

T1 - Restoration of energy homeostasis by SIRT6 extends healthy lifespan

AU - Roichman, A.

AU - Elhanati, S.

AU - Aon, M. A.

AU - Abramovich, I.

AU - Di Francesco, A.

AU - Shahar, Y.

AU - Avivi, M. Y.

AU - Shurgi, M.

AU - Rubinstein, A.

AU - Wiesner, Y.

AU - Shuchami, A.

AU - Petrover, Z.

AU - Lebenthal-Loinger, I.

AU - Yaron, O.

AU - Lyashkov, A.

AU - Ubaida-Mohien, C.

AU - Kanfi, Y.

AU - Lerrer, B.

AU - Fernández-Marcos, P. J.

AU - Serrano, M.

AU - Gottlieb, E.

AU - de Cabo, R.

AU - Cohen, H. Y.

PY - 2021/5/28

Y1 - 2021/5/28

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85106979443&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-23545-7

DO - 10.1038/s41467-021-23545-7

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 34050173

AN - SCOPUS:85106979443

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3208

ER -

Restoration of energy homeostasis by SIRT6 extends healthy lifespan

Abstract

Bibliographical note

Funding

Access to Document

Other files and links

Fingerprint

Genomics

Cite this

Restoration of energy homeostasis by SIRT6 extends healthy lifespan

Abstract

Bibliographical note

Funding

Access to Document

Other files and links

Fingerprint

Equipment

Genomics

Cite this