The long-term objective of this research is to gain an understanding of the process of cellular aging at the molecular level. To this end, budding yeast will be developed as an experimental system for the analysis of replicative mortality. This major goal of the project will be realized by establishing affinity chromatography techniques for the fractionation of cell populations on the basis of age. These techniques, appropriately modified, will be used to select and to screen for mutants that display an altered life-span. Mutations that lead either to premature senescence or to longevity, including immortalization, will be identified. In addition to these efforts, the question of whether a genetic (developmental) program for cellular aging exists will be addressed. This problem will be studied by searching for differential gene expression during aging with the use of molecular cloning techniques. Finally, three specific aspects of cellular physiology will be examined as a function of cell age. These will include: transposition events, the function and structural integrity of the DNA replicative complex, and the generation of extrachromosomal DNA circles. The proposed studies should provide insights into the molecular cell biology of the aging process, and they may allow an evaluation of the relative contributions of genetic programs and random errors to cellular senescence. Most importantly, they should result in the development of an experimental system in which the tools of genetics, both molecular and classical, can augment the cellular and molecular approach to the complex problem of cell senescence. The proposed research is directly applicable to the area of aging in humans, and it also is relevant to the cancer problem.
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