PROJECT SUMMARY Cellular senescence is a multi-faceted stress response that has become increasingly implicated as a driver of aging and many age-related pathologies. This proposal aims to renew a long-standing grant that has supported our work to understand the basic physiological and pathophysiological consequences of the senescence response. Through the use of simple and complex human and mouse cell cultures and a newly described mouse model developed by us, we propose a series of experiments that will provide a more in-depth understanding of the relationship between senescent cells, their presence and phenotypes during organismal aging, and aging phenotypes. We propose to provide answers to three crucial outstanding questions in aging research that have been unanswerable until recently. First, what are the occurrences, sub-tissue localization, cell type-specificities and phenotypic characteristics of senescent cells that accumulate during aging across tissues? Second, what are the phenotypes of senescent cells that accumulate in during aging compared to those that occur during wound healing? And finally, what is the impact of senescent cells on the apparent stochastic variation in aging phenotypes and life span among genetically identical mice? Together, these aims will fill crucial gaps in our knowledge about how senescent cells contribute to aging phenotypes and, consequently, organismal health span and ultimately life span.