(04-12-10) Sirt3 Mediates Reduction of Oxidative Damage and Prevention of Age-Related Hearing Loss under Caloric Restriction

Authors
Shinichi Someya, Wei Yu, William C. Hallows, Jinze Xu, James M. Vann, Christiaan Leeuwenburgh, Masaru Tanokura, John M. Denu , Tomas A. Prolla See Affiliations
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Departments of Genetics and Medical Genetics, University of Wisconsin, Madison, WI 53706, USA Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI 53706, USA Department of Applied Biological Chemistry, University of Tokyo, Yayoi, Tokyo 113-8657, Japan Department of Aging and Geriatrics and The Institute on Aging, University of Florida, Gainesville, FL 32611, USA Corresponding author These authors contributed equally to this workHighlights
? Sirt3 mediates prevention of age-related hearing loss under caloric restriction
? Sirt3 mediates reduction of oxidative damage under caloric restriction
? Sirt3 deacetylates and activates mitochondrial Idh2 under caloric restriction
? Sirt3 enhances the glutathione antioxidant defense system under caloric restriction
Summary
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.

Source: Cell, 22 November 2010

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