Abstract: Our studies in yeast have shown that the down-regulation of major signal transduction mediators increases stress resistance and causes chronological lifespan extension up to 10-fold. Whereas other laboratories have proposed that sirtuins (Sir2 and its homologs), a family of conserved proteins which are NAD(+)-dependent histone deacetylases, can extend longevity in various model organisms, we propose that one sirtuin, i.e., Sir2, can also accelerate cellular aging and death. In Saccharomyces cerevisiae (yeast), the omission of Sir2 increases DNA damage but in combination with longevity mutations in principal intracellular signal transduction mediators, or in combination with calorie restriction it causes a further increase in the chronological lifespan as well as an increase in the stress resistance and a major reduction in age-dependent genomic instability. Our recent results also provide evidence for a role of the mammalian Sir2 ortholog SirT1 in the activation of a highly conserved neuronal pathway and in the sensitization of neurons to oxidative damage. However, the mean lifespan of the SirT1(+/-) mice was not different from that of wild type animals, and the survival of SirT1(-/-) mice was reduced under both normal and calorie restricted conditions. Here, I review the studies linking SirT1, IGF-I signaling and starvation in various model organisms with a focus on the post-mitotic cells, which indicate that sirtuins can play both protective and pro-aging roles.