In C. elegans, the germline stem cells; that is, the cells that give rise to sperm and oocytes, influence the aging process. Killing the germline precursors extends lifespan approximately 60%. This lifespan extension is not simply due to sterility, because killing the precursors of the entire reproductive system (the germline as well as the somatic gonad) has no effect on lifespan. In order for germline-ablation to extend lifespan, the DAF-16 protein, a forkhead-family transcription factor, is required. Thus, lifespan extension requires changes in transcription. In addition, the animals also require a functional DAF-12 steroid hormone receptor homologue. Thus, germline stem cells may exert their effects on aging by regulating asteroid hormone. By using mutations to eliminate specific subsets of germ cells (sperm, oocytes, germline stem cells), we have found that the germline stem cells regulate aging in adult animals. If the germline stem cells are forced to exit mitosis and enter meiosis in adult animals, lifespan is extended. In this study, we will investigate the mechanism by which germline stem cells influence the aging process. We will determine the sites of action of DAF-16 and DAF-12 activity, and we will identify downstream targets of these genes that extend lifespan using microarray analysis. In addition, we will screen for new genes that function in this pathway, and we will begin to determine their molecular activities and their times and sites of action. These studies could define pathways that regulate aging not only in C. elegans, but also in higher organisms, including humans. Using this information, it may be possible to improve the quality of old age, and to delay the onset of age-related diseases, such as cancer and diabetes. In addition, our findings may yield insights into the ways that stem cells can influence endocrine signaling in vertebrates.
