Sirt3 Mediates Reduction of Oxidative Damage and Prevention of Age-related Hearing Loss Under Caloric Restriction

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2010 Nov 25

PMID 21094524

Citations 586

Authors

Shinichi Someya

Wei Yu

William C Hallows

Jinze Xu

James M Vann

Christiaan Leeuwenburgh

Masaru Tanokura

John M Denu

Tomas A Prolla

Affiliations

Soon will be listed here.

Abstract

Caloric restriction (CR) extends the life span and health span of a variety of species and slows the progression of age-related hearing loss (AHL), a common age-related disorder associated with oxidative stress. Here, we report that CR reduces oxidative DNA damage in multiple tissues and prevents AHL in wild-type mice but fails to modify these phenotypes in mice lacking the mitochondrial deacetylase Sirt3, a member of the sirtuin family. In response to CR, Sirt3 directly deacetylates and activates mitochondrial isocitrate dehydrogenase 2 (Idh2), leading to increased NADPH levels and an increased ratio of reduced-to-oxidized glutathione in mitochondria. In cultured cells, overexpression of Sirt3 and/or Idh2 increases NADPH levels and protects from oxidative stress-induced cell death. Therefore, our findings identify Sirt3 as an essential player in enhancing the mitochondrial glutathione antioxidant defense system during CR and suggest that Sirt3-dependent mitochondrial adaptations may be a central mechanism of aging retardation in mammals.

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