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Sirt3 Mediates Reduction of Oxidative Damage and Prevention of Age-Related Hearing Loss under Caloric Restriction
Shinichi Someya1, 3, 5, Wei Yu2, 5, William C. Hallows2, Jinze Xu4, James M. Vann1, Christiaan Leeuwenburgh4, Masaru Tanokura3, John M. Denu2, , and Tomas A. Prolla1, ,
1 Departments of Genetics and Medical Genetics, University of Wisconsin, Madison, WI 53706, USA
2 Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI 53706, USA
3 Department of Applied Biological Chemistry, University of Tokyo, Yayoi, Tokyo 113-8657, Japan
4 Department of Aging and Geriatrics and The Institute on Aging, University of Florida, Gainesville, FL 32611, USA
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 s 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.
