Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction
- PMID: 21094524
- PMCID: PMC3018849
- DOI: 10.1016/j.cell.2010.10.002
Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction
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.
Copyright © 2010 Elsevier Inc. All rights reserved.
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Comment in
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SIRT3 in calorie restriction: can you hear me now?Cell. 2010 Nov 24;143(5):667-8. doi: 10.1016/j.cell.2010.11.009. Cell. 2010. PMID: 21111225
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Sirtuins and calorie restriction.Nat Rev Mol Cell Biol. 2012 Feb 29;13(4):207. doi: 10.1038/nrm3308. Nat Rev Mol Cell Biol. 2012. PMID: 22374145 No abstract available.
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