The studies outlined in this proposal address fundamental issues of the biology of aging, specifically focused on the molecular characteristics, mechanisms and consequences of stem cell aging. Based on mutual interests and complementary areas of expertise, the three laboratories of this Program form a cohesive, collaborative team to address these basic questions. With expertise in stem cells in skeletal muscle (Rando laboratory, Project 1), epithelial stem cells (Artandi laboratory. Project 2), and neural stem cells (Brunet laboratory. Project 3), the Program has the following Specific Aims: 1) to understand the underlying molecular mechanisms that regulate stem cell function and that are responsible for declining stem cell function with age; 2) to characterize the transcriptional networks and epigenetic profiles in stem cells from different tissues; and 3) elucidate the age-related changes that are common among different stem cell populations and changes that are unique to stem cells in particular tissues. These Overall Aims are reflected in the Specific Aims of each Project, with emphases on the role of signaling pathways that regulate stem cell function. The major pathways to be explored in multiple Projects are the Wnt signaling pathway which has recently been shown to contribute to tissue aging by suppression of stem cell functionality, Telomerase and novel functions of the protein component (TERT) in regulating stem cell function and regulating Wnt signaling, and the Foxo transcription factors which regulate organismal aging. All of these will be examined in all three of the Projects, exploring mechanisms of co-regulation of genes that regulate stem cell function, and focusing on the causes and consequences of changes in transcriptional programs that determine age related changes in stem cell functionality. Of particular interest is the identification of mechanisms of stem cell aging that are shared among different stem cell populations. Within that context, all Projects will examine transcriptional networks and regulatory mechanisms, including epigenetic processes, that govern stem cell function and that drive changes with age. These broad goals will be supported by an Administrative Core and two Scientific Cores - a Mouse Aging Core and a Genomics and Ultra-High-Throughput Sequencing Core. The collaborative and coordinated efforts of the three laboratories participating in this Program are uniquely situated within the outstanding research environment of Stanford University to work at the interface between stem cell biology and the biology of aging to create a highly effective and synergistic research program focused on the molecular mechanisms of stem cell aging.