Restoration of energy homeostasis by SIRT6 extends healthy lifespan

Asael Roichman ,Yael Shahar ,Miguel A Aon ,Manuel Serrano ,Sivan Elhanati ,Alexey E Lyashkov ,Andrea Di Francesco ,Zachary Petrover ,Pablo J Fernández-Marcos ,Ariel M Rubinstein ,Orly Yaron ,Ceereena Ubaida‐Mohien ,Matan Y Avivi ,Ifat Abramovich ,Adi Shuchami ,Ilana Lebenthal-Loinger ,Eyal Gottlieb ,Yosri Wiesner ,Yariv Kanfi ,Rafael De Cabo ,Batia Lerrer ,Maor Shurgi ,Haim Y Cohen

doi:10.1038/s41467-021-23545-7

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.

Highlights

Aging leads to a gradual decline in physical activity and disrupted energy homeostasis
To explore the role of SIRT6 and its interaction with SIRT1 in aging, the lifespan of SIRT1, SIRT6, and SIRT1 + SIRT6-overexpressing C57BL/6JOlaHsd transgenic male and female mice were compared to their wild-type (WT) littermates
We showed that SIRT6 overexpression in mixed-CB6 background extend only male lifespan[29]

Summary

Introduction

Aging leads to a gradual decline in physical activity and disrupted energy homeostasis. We show that SIRT6 overexpression leads to a reduction in frailty and lifespan extension in both male and female B6 mice. 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. 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. Activation of pathways which sense a low-energy state, such as AMP kinase (AMPK) and sirtuins lead to increased longevity in a wide range of organisms[6]

Methods

Results

Conclusion