Sir2 Blocks Extreme Life-Span Extension

Cell. 2005 Nov 18;123(4):655-67. doi: 10.1016/j.cell.2005.08.042.

Abstract

Sir2 is a conserved deacetylase that modulates life span in yeast, worms, and flies and stress response in mammals. In yeast, Sir2 is required for maintaining replicative life span, and increasing Sir2 dosage can delay replicative aging. We address the role of Sir2 in regulating chronological life span in yeast. Lack of Sir2 along with calorie restriction and/or mutations in the yeast AKT homolog, Sch9, or Ras pathways causes a dramatic chronological life-span extension. Inactivation of Sir2 causes uptake and catabolism of ethanol and upregulation of many stress-resistance and sporulation genes. These changes while sufficient to extend chronological life span in wild-type yeast require severe calorie restriction or additional mutations to extend life span of sir2Delta mutants. Our results demonstrate that effects of SIR2 on chronological life span are opposite to replicatve life span and suggest that the relevant activities of Sir2-like deacetylases may also be complex in higher eukaryotes.

Publication types

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

MeSH terms

  • Adenylyl Cyclases / genetics
  • Alcohol Dehydrogenase / metabolism
  • DNA Repair
  • Down-Regulation / genetics
  • Ethanol / metabolism
  • Ethanol / pharmacology
  • Gene Deletion
  • Gene Expression Profiling
  • Gene Expression Regulation, Fungal / genetics
  • Histone Deacetylases / genetics
  • Histone Deacetylases / physiology*
  • Hot Temperature
  • Hydrogen Peroxide / pharmacology
  • Models, Biological
  • Mutation / genetics
  • Oxidative Stress
  • Protein Kinases / genetics
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / physiology*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / physiology
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae / genetics
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae / physiology*
  • Sirtuin 2
  • Sirtuins / genetics
  • Sirtuins / physiology*
  • Time Factors
  • Up-Regulation / genetics
  • Vitamin K 3 / pharmacology

Substances

  • Saccharomyces cerevisiae Proteins
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae
  • Ethanol
  • Vitamin K 3
  • Hydrogen Peroxide
  • Alcohol Dehydrogenase
  • Protein Kinases
  • SCH9 protein kinase
  • SIR2 protein, S cerevisiae
  • Sirtuin 2
  • Sirtuins
  • Histone Deacetylases
  • Adenylyl Cyclases