Six fold Life Span Extension by Double Mutations in SIR2 and SCH9 or RAS2/CYR1.
Paola Fabrizio, Valter Longo
Biological Sciences, University of Southern California, 3715 McCLintock, Los Angeles, CA, 90089, USA
Overexpression of Sir2-like deacetylases can delay aging in yeast and other organisms. We show that down-regulation of glucose signaling or calorie restriction can turn Sir2 from an anti- to a pro-aging gene. Lack of Sir2 deacetylase activity in combination with starvation or mutations in either the SCH9 or RAS2/CYR1 pathways causes an up to six fold life span extension and a major decrease in age-dependent DNA mutations. The effect of sir2? on life span is mediated in part by an early deacetylase-dependent activation of alcohol dehydrogenase 2 (ADH2) and the uptake of extracellular ethanol and is associated with up-regulation of many stress resistance and sporulation genes. Parallel studies in rat cortical neurons show increased oxidative stress resistance upon treatment with Sir2/Sirt1 inhibitors, suggesting that this deacetylase can also play a pro-aging role in mammals. These results indicate that Sir2 can block entry into an extreme longevity extension phase triggered by starvation or down-regulation of the Sch9 or Ras/Cyr1/PKA pathways.