ABSTRACTMitochondrial sirtuins regulate biochemical pathways and are emerging drug targets for metabolic and age-related diseases such as cancer, diabetes, and neurodegeneration. Yet, their functions remain unclear. Here, we uncover a novel physiological role for the C. elegans mitochondrial sirtuins, sir-2.2 and sir-2.3, in lifespan regulation. Using a genetic approach, we demonstrate that sir-2.2 and sir-2.3 mutants live 28-30% longer than controls when fed the normal lab diet of E. coli OP50. Interestingly, this effect is diet specific and is not observed when animals are fed the strain HT115, which is typically used for RNAi experiments. While decreased consumption of food is a known mechanism for lifespan extension, this does not account for the increased lifespan in the mitochondrial sirtuin mutants. sir-2.2 and sir-2.3 mutants display altered expression of genes involved in oxidative stress response, including increased expression of the mitochondrial superoxide dismutase sod-3 and decreased levels of catalases ctl-1 and ctl-2. Like their extended lifespan phenotype, these alterations in oxidative stress gene expression are diet dependent. The mitochondrial sirtuin mutants are more resistant to the lifespan extending effects of low levels of superoxide, suggesting that their increased lifespan involves a hormetic response. Our data suggest that sir-2.2 and sir-2.3 are not completely redundant in function and may possess overlapping yet distinct mechanisms for regulating oxidative stress response and lifespan.
4-PHENYLBUTYRATE: MOLECULAR MECHANISMS AND AGING INTERVENTION POTENTIAL
