Studies of the basic mechanisms of aging have led to the identification of many genes modulate life span in model organisms. Despite these advances, however, the molecular mechanism(s) that determine human longevity and susceptibility to age-associated disease remain poorly understood. We have taken a large-scale, multi-organism approach to address the question of which genes and pathways identified in model organisms are most likely to be relevant for human aging. The rationale this approach is that, if a particular gene or pathway plays a similar aging-related role in different model organisms, then it is likely that the function of the gene or pathway has been conserved in people. Thus far, we have identified 25 genes that function similarly to determine longevity in two very different organisms: the single-celled budding yeast and the multicellular nematode worm. In this proposal, we will use a combination of genetic and molecular approaches to understand the mechanistic basis for how these genes determine life span in both yeast and worms, and to place them into conserved longevity pathways. These studies will define the most important evolutionarily conserved mechanisms of aging and will lead to new hypotheses that can be tested in future studies in mammals.