Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction

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 AH...

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Vydáno v:Cell Ročník 143; číslo 5; s. 802
Hlavní autoři: Someya, Shinichi, Yu, Wei, Hallows, William C, Xu, Jinze, Vann, James M, Leeuwenburgh, Christiaan, Tanokura, Masaru, Denu, John M, Prolla, Tomas A
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 24.11.2010
Témata:
Aging - metabolism
Animals
Antioxidants - metabolism
Caloric Restriction
DNA Damage
Female
Glutathione - metabolism
Hearing Loss - prevention & control
Isocitrate Dehydrogenase - metabolism
Male
Mice
Mice, Inbred C57BL
Mitochondria - metabolism
Oxidative Stress
Sirtuin 3 - genetics
Sirtuin 3 - metabolism
ISSN:1097-4172, 1097-4172
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Shrnutí: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.
Bibliografie:ObjectType-Article-1
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2010.10.002