Extrachromosomal rDNA circle (ERC) accumulation has been shown to be a cause of yeast aging. To determine whether ERC accumulation is the only cause of yeast aging, and to learn more about how ERC lead to aging, we set out to identify long-lived mutants and to reveal the mechanisms by which they extend longevity. In a pilot study, we found that several mutants of the cyclic AMP/protein kinase A pathway exhibited prolonged life spans. The cAMP/PKA pathway controls many cellular processes that have also been implicated in aging. Yeast cells with attenuated cAMP/PKA activity exhibit enhanced stress gene expression and a slowing of metabolism, a condition that may be similar to caloric restriction. Thus, this pathway may serve as the key signaling pathway that affects the rate of aging. In this regard, it will be very interesting to study how this pathway affects life spans and whether it involves ERC accumulation. The overall goals of this proposal are: 1) To determine the genetic and molecular pathways leading to prolonged life spans in mutants with compromised cAMP/PKA activity such as the cdc35-1 mutant, and 2) to further study the molecular pathways of aging by a genetic screen for long-lived mutants.