The CDC projects that in the next twenty years, the percent of Americans aged 65 or older will double, creating a surge in the incidence of age-related health disorders. To deal with this emerging health and economic challenge, the CDC has called for an "enhanced focus on promoting and preserving the health of older adults". The experiments proposed in this application seek to determine the genetic basis of organismal aging in order to develop therapies to improve and preserve the health of the aging human population. We will focus more specifically on identifying the biological mechanisms by which increased dosage of the gene encoding the short isoform of p53 (p44) accelerates the rate of aging in the mouse. The tumor suppressor p53 appears to have a paradoxical effect on health and lifespan. p53 is absolutely required to prevent death from cancer in mice, yet an unregulated increase in p53 activity reduces the lifespan of both mouse and Drosophila models. Human studies have identified a p53 polymorphism which confers a significant increase in lifespan despite the fact that carriers suffer from higher rates of cancer mortality. We propose that the short isoform of p53 (p44) controls organismal aging by regulating stem cell self-renewal and that longevity can be extended by reducing the level of p44 relative to p53. We will test this hypothesis using three main aims. First we will use cell-based assays to examine stem cell self-renewal and differentiation in response to varying doses of p44. These experiments should uncover the role of p44 in stem cell self-renewal and maintenance of tissue homeostasis, two critical determinants of organismal aging. Next we will generate mice with normal p53 but reduced p44 to determine if organismal longevity can be extended by lowering the level of p44 relative to p53. Finally, we will evaluate neurogenesis using neural stem cells from animals with reduced p44 to discover how this particular tissue homeostasis program responds to a reduction in p44. In addition to the relevance to aging research, the experiments described here will provide valuable data on the role of p44 in stern cell behavior. Recent studies have shown that a variety of tumors are initiated by malignant cells with the characteristics of stem cells, so called "cancer stem cells". We anticipate that our studies on the role of p44 in stem cell self-renewal may also provide data that will be useful in future studies targeting the growth of the cancer stem cells that cause tumors. The results obtained from these experiments will provide critical insights into how p44 regulates mammalian longevity and will enable the field to focus future efforts on defined cellular pathways.