INVESTIGATION OF COMPARTMENTAL PDHX IN CELLULAR SENESCENCE The capacity to maintain homeostasis determines the overall health of the cell and the dysregulation of this process can culminate into loss of cellular function and tissue deterioration ultimately leading to organismal aging. Aging is a highly complex process with several distinct cellular hallmarks which include epigenetic alteration, mitochondrial dysfunction, nutrient sensing, and cellular senescence. While these aging associated biological processes are distinct, they are highly interconnected as the perturbation of one hallmark will affect one or multiple other age-related processes. Cellular senescence, the process where a cell limits its proliferative ability and ceases to divide is a hallmark of aging and implicated in age-related diseases. Senescent cells undergo a rewiring of its chromatin landscape as well as its metabolism. While studies have addressed these changes individually, few have examined the crosstalk of these metabolism and epigenetics in cellular senescence. Metabolic enzymes and complexes have been known to regulate chromatin by providing pools of metabolites that can be utilized by epigenetic enzymes for their catalytic activity. To uncover potential metabolic- epigenetic axis in senescence, I performed a metabolic targeted CRISPR library screen in replicative senescence and identified the deletion of Pyruvate Dehydrogenase Complex Component X (PDHX) delays senescence. PDHX is a component of the pyruvate dehydrogenase complex and is primarily localized within the mitochondria, however, we identified that a nuclear isoform is upregulated in senescence and PDHX increases its association with chromatin during senescence. Immunoprecipitation of PDHX in the mitochondria as compared to the nucleus indicates distinct protein interactions suggesting unique compartmental functions. Due to the function of PDHX in metabolism and our preliminary data of its interaction on chromatin, we hypothesize PDHX plays a key function in coordinating metabolism and chromatin dynamics required for cellular senescence. Thus, the completion of the proposal will identify help elucidate a potential crosstalk between metabolism and epigenetics in senescence and aging.