Age is a major risk factor for many diseases including cancer, cardiovascular disease, neurodegeneration, and type II diabetes. Recent research has identified universal mechanisms that determine and regulate organismal aging, and impact all organ systems. Understanding the fundamental processes of aging is expected to provide therapeutic targets to delay the onset of many age-associated diseases. Emerging evidence suggests that cellular senescence contributes to the physiological process of organismal aging. Cellular senescence refers to the irreversible growth arrest that is triggered by telomere shortening and also by a variety of cellular stresses. The Polycomb group protein Enhancer of Zeste Homolog 2 (EZH2), a methyltransferase that catalyzes the tri-methylation of histone 3 at lysine 27 (H3K27me3), has been implicated in regulating cellular senescence. The long-term objective of my research is to understand the molecular processes that contribute to senescence. Specifically, I propose here a series of mechanistic experiments and genome-wide analyses to investigate the mechanisms by which EZH2 regulates cellular senescence. Aim 1 will examine the connections between EZH2 and the Wnt signaling pathway, a known regulator of cellular senescence, using knockdown and overexpression strategies. Aim 2 will investigate the mechanism by which repression of EZH2 triggers the increase in reactive oxygen species. Aim 3 will examine the changes in global chromatin structure that are triggered during senescence induced by the downregulation of EZH2. My studies will help define novel mechanisms by which epigenetic changes impact and regulate cellular senescence. This knowledge is expected to open new avenues for interventions to delay age-associated diseases and increase human health span.