Abstract Project Summary ! Age-related stem cell dysfunction is thought to contribute to diminished heath, tissue degeneration, and cancer. The stem cell niche is required to maintain stem cells, and both the niche and stem cells age. To potentially reverse deleterious effects of stem cell aging and to predict how regenerative medicine strategies such as stem cell replacement will be influenced by an aged niche environment, we need to understand how aging affects the entire unit, including the niche. Local stem cell niches physically interact with and signal to stem cells, and aging can alter these niche-stem interactions. Yet it is not well understood how these aspects of the aging niche combine to contribute to age-related stem cell decline nor how they can be reversed to potentially rejuvenate aged stem cells. This project uses a combination of imaging, molecular-genetic, and cell biological approaches in C. elegans, an established model organism for aging biology that has an anatomically well-defined and accessible niche that supports germline stem cells. Thus the project has implications for reproductive aging as well. The project will elucidate how aging impacts the niche and its responding stem cells, discover the molecular mechanisms driving niche aging, and determine the potential of niche manipulation to rejuvenate stem cells. In addition, it will address how this niche-stem system integrates with a novel branch of the systemic insulin aging pathway that was previously implicated in stem cell aging in this system. !