The budding yeast S. cerevisiae provides a surprising and remarkably useful model for longevity studies,because certain genetic and metabolic pathways regulating aging in yeast are evolutionarily conserved inmetazoans, even in humans. In particular yeast provides a tractable genetic model for replicative aging,since yeast cells divide a certain number of times and then cease to replicate. A number of observationssuggest that alterations in chromatin structure, including changes in histone covalent post-translationalmodifications, occur as yeast age. For example, experimental manipulation of Sir2 levels, a deacetylase thattargets histones, changes the kinetics of aging - loss of Sir2 causes more rapid aging and over-expression ofSir2 causes delayed aging. However, whether chromatin changes are an important aspect of agingjs notwell understood.Our hypothesis is that alterations of histone post-translational modifications and changes in chromatinstructure cause decompaction of heterochromatic regions of the genome during yeast replicative aging andmay directly contribute to the aging phenotype. We further hypothesize that the chromatin changes areepigenetic, in that they are a stable, inherited attribute of the aging yeast cell. In the proposed research wewill test these hypotheses via several specific aims. (1) Our first goal is to determine whether Sir2deacetylation of histone H416ac (a well-characterized substrate of Sir2) has a central physiological role toantagonize yeast aging. We will determine whether deacetylation of H4K16ac maintains compaction ofheterochromatic regions in young yeast, and will investigate the mechanism of gradual decompaction as akey change in chromatin underlying aging. (2) Second, we will examine whether regulation of Sir2 is acritical aspect of aging. Sir2 function is reduced during yeast and metazoan aging, however the mechanisticbasis of this has not been elucidated. We will determine whether the activity, regulation, and localization ofSir2 are altered, and if small molecule effectors can regulate Sir2 function during aging. (3) Finally, we willinvestigate a wider role of chromatin changes during aging including additional histone modifications,nucleosome remodeling, and altered histone composition.We will collaborate extensively with the other Projects within this Program. We will collaborate withProject 1 (R. Marmorstein) to examine physiological and small molecule activators and inhibitors of Sir2during aging. We will collaborate with Project 3 (B. Johnson) to test conservation of Sir2 mechanisms inyeast replicative aging and replicative senescence in the telomerase deficiency model. We will collaboratewith Project 4 (P. Adams) to investigate possible conservation in yeast of histone chaperone proteincomplexes relevant to heterochromatic foci that occur in the mammalian bone senescence model.
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