Aging is the major risk factor for many human cancers. However, the mechanisms responsible for the effect of aging on tumor incidence are poorly understood, in part because few model systems are available to study age-dependent genomic instability . Furthermore, the role of DNA mutations in "normal aging" and "life span extension" is unclear. We will test the hypothesis that the histone deacetylase Sir2, and the signal transduction proteins Ras and Sch9 synergistically regulate aging and genomic instability in S. cerevisiae. We propose that the effect of Sir2, Sch9, and Ras2 on chronological life span and genomic instability is mediated in part by the down-regulation of enzymes that repair DNA. Finally, we will test the role of different DNA repair systems in chronological aging and life span extension. My laboratory has developed a novel method to study aging in yeast based on the survival of non-dividing populations (chronological life span). This system allowed us to identify two pathways that regulate longevity in yeast: the Ras and Sch9 pathways. Notably yeast Ras2 and Sch9 are functional homologs of mammalian Ras and Akt, two of the major human oncogenes. Akt also functions in insulin-like pathways that regulates longevity in C. elegans, Drosophila, and mice. Thus, chronologically aging S. cerevisiae can serve as a model to identify genes that regulate genomic instability and understand the mechanisms responsible for age-dependent DNA mutations and cancer in mammals. [unreadable] [unreadable] [unreadable]