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

Cell. 2010 Nov 24;143(5):802-12. doi: 10.1016/j.cell.2010.10.002.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • Antioxidants
  • Sirt3 protein, mouse
  • Isocitrate Dehydrogenase
  • Sirtuin 3
  • Glutathione