PROJECT SUMMARY The progressive decline in the function of adult stem cells is a major factor in the development of age-related conditions. Considering the increasing age of the overall human population, identifying strategies to prolong stem cell health is of major importance. Study of short-lived model systems has identified many potential limiting factors in the maintenance of stem cells, but has been unable to elucidate whether and how stem cell aging could be avoided altogether. We will leverage the negligibly senescent system S. mediterranea to reveal the regulation underlying this animal’s ability to maintain stem cell health seemingly indefinitely. We previously found that planarian stem cells employ a double layer of protection against transposons, whereas the shorter- lived differentiated cells retain only a single defense layer, suggesting that transposons could be a significant threat to stem cell maintenance. Further, loss of transposon silencing leads to rapid lethality in these otherwise long-lived animals. This project focuses on the role of transposon silencing and chromatin compaction in the resistance to aging phenotypes of planarian tissues. We intend to leverage our recent finding of stereotypic age-related markers in planarian differentiated cells to determine the role of various pathways in the progression of planarian aging. Aim 1 of this proposal seeks to elucidate whether changes in transposon levels or in chromatin regulation can change the rate of aging in planarian differentiated tissues. Aim 2 addresses the role of various transposon-related pathways in the indefinite maintenance of planarian stem cells. Aim 3 will determine whether there is a correlation between the lifespan of a planarian tissue type and its control of transposons. Furthermore, the genomic locations of age-related changes in chromatin modifications will be addressed. This project will provide new insights in the workings of a negligibly senescent system. Understanding of the mechanisms it employs in the long-term maintenance of its actively dividing stem cell population will provide new avenues to pursue in search for strategies to extend human stem cell health.