This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cellular aging and apoptosis are two processes that have been implicated in human disease. For instance, it is now clear that both are potent anti-cancer mechanisms. Cells that either escape senescence or bypass apoptosis in response to oncogenic stimuli can undergo malignant transformation. The ability of cells to evade programmed cell death has been called a 'hallmark of cancer'. Significantly, there is good evidence that disabling mutations senescence and apoptosis contribute to the anti-tumor activity of many chemotherapeutic drugs and that apoptosis can result in multi-drug resistance. The budding yeast Saccharomyces cerevisiae has served as a useful model for complex physiological processes of metazoan cells, including aging and apoptotic cell death. Molecular mechanisms of both these processes appear to be conserved and genetic determinants have been identified in yeast with orthologues in higher organisms. This research program outlines several genetic strategies to identify molecular links between these two processes in yeast. It will exploit the primary advantage of the yeast system over its mammalian counterpart as a model system for aging because yeast cells represent aging-related processes typical of higher organisms but age more quickly. Yeast cells are easier to work with because they age and reach senescence within a matter of weeks. Mammalian cells, on the other hand, take months to undergo senescence, while mammalian organisms take years, if not decades, to age. Given the remarkable conservation of the aging and apoptotic pathways across diverse species, this analysis, which takes advantage of the genetic tools and ease of study associated with the yeast system, should lead to further insights into the analogous processes in higher organisms including human beings.
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