The broad aims of this proposal are to study aging, senescence, and cell death in a simple microbial organism that is amenable to genetic analysis. Yeast may be an excellent model system for these studies, because many aspects of cell biology are conserved down to a mechanistic level in many eukaryotes, including yeast and mammals. The budding yeast, Saccharomyces cerevisiae, divide asymmetrically, giving rise to a large mother cell and a small daughter cell at each cell division. Mother cells have a fixed life span, i.e. give rise to a fixed number of daughters. These daughters reset to a normal full life span. Further, mother cells exhibit morphological changes as they age notably, cell enlargement. Finally, senescent mother cells may undergo a program of cell death similar to apoptosis in mammalian cells. Four aspects of the aging process will be studied in budding yeast, First, the fixed life span of mothers will be investigated. Mutants in which mothers give rise to many more daughters than do wild type mothers will be isolated ("long lived mutants"). Second, the ability of daughters to reset to a full life span will be studied. Mutants in which daughters do not reset will be isolated ("resetting mutants"). Third, morphological changes that cells undergo as they age will be probed. Mutants which do not undergo changes, such as cell enlargement as they grow old, will be isolated. Fourth, programmed cell death, or apoptosis, will be analyzed. Mutants that do not undergo morphological changes associated with cell death will be isolated. The genes identified in these various genetic selections and screens will be cloned and sequenced. Functional relevance of these genes to aging, senescence, and cell death in higher organisms will be evaluated.