Mutations in the Sch9 and Ras/cAMP signal transduction pathways, which promote reproduction in response to glucose/nutrients, activate multiple stress resistance systems and extend the life span of non-dividing yeast by up to three-fold. Sch9 is homologous to the C. elegans, Drosophila, and mammalian serine/threonine kinases Akt/PKB, which are also activated in response to glucose/nutrients and function in pathways that regulate reproduction and longevity. I propose that the modulation of analogous signal transduction pathways can increase resistance to damage and extend longevity in organisms ranging from yeast to mammals by shifting the investment of energy from growth and reproduction to multiple stress resistance systems. These mechanisms may have arisen early during evolution in order to minimize aging during periods of starvation. To test this hypothesis I propose to: 1) elucidate the molecular mechanisms responsible for the regulation of longevity by the yeast Ras/cAMP and Sch9 pathways, focusing on known stress resistance genes and on yeast homologs of genes that function in the IGF-1/insulin signaling pathway in higher eukaryotes, 2) perform unbiased screens and study uncharacterized stress resistant mutants isolated in previous screens to identify novel genes that mediate longevity-regulation downstream of Ras/cAMP/Msn2/4 and Sch9, 3) characterize further the post-diauxic life span in wild type and long-lived mutants to understand the relationship between aging in yeast and in higher eukaryotes, 4) identify the distinct mechanisms that regulate the """"""""chronological life span"""""""" (survival of non-dividing yeast) and """"""""replicative life span"""""""" (budding potential). The combination of the short, high-metabolism post-diauxic life span with transposon mutagenesis provides a rapid method to identify the mediators of stress resistance and longevity extension. The identification and characterization of these mutations should contribute to the identification and understanding of putative dormant starvation-response pathways in mammals, which may be activated to protect cells against aging and age-related diseases without affecting normal functions.
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