DIVERGENT ROLES OF RAS1 AND RAS2 IN YEAST LONGEVITY

Individual cells of the yeast Saccharomyces cerevisiae have a limited replicative life-span. The role of the genes RAS1 and RAS2 in yeast lo ngevity was examined. Overexpression of RAS2 led to a 30% increase in the life-span on average and postponed the senescence related increase in generation time seen during yeast aging. No life-span extension wa s obtained by overexpression of RAS1. However, deletion of RAS1 prolon ged the life-span. These results suggest that RAS1 and RAs2 play recip rocal roles in determining yeast longevity. RAS1 and RAS2 mRNA and pro tein levels declined with replicative age, suggesting a diminishing im pact on yeast longevity. The major known pathway through which Ras pro teins function in yeast involves stimulation of adenylate cyclase. No evidence for a life-span-extending effect of elevated intracellular cA MP was found. Indeed, high intracellular cAMP was associated with curt ailed lifespan. A similar decrease in life-span was found on disruptio n of BCY1, which codes for the regulatory subunit of protein kinase A, the downstream target of cAMP. Importantly overexpression of an effec tor domain mutant of RAS2, defective in stimulation of adenylate cycla se, prolonged life-span to the same extent as the wild-type gene, sugg esting that the cAMP pathway is neither sufficient nor necessary for i ncreased longevity.