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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG020932-05
Application #
7113194
Study Section
Special Emphasis Panel (ZAG1-FAS-9 (J2))
Program Officer
Mccormick, Anna M
Project Start
2002-09-01
Project End
2007-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
5
Fiscal Year
2006
Total Cost
$369,849
Indirect Cost
Name
University of California San Francisco
Department
Biochemistry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Yamawaki, Tracy M; Berman, Jennifer R; Suchanek-Kavipurapu, Monika et al. (2010) The somatic reproductive tissues of C. elegans promote longevity through steroid hormone signaling. PLoS Biol 8:
Ghazi, Arjumand; Henis-Korenblit, Sivan; Kenyon, Cynthia (2009) A transcription elongation factor that links signals from the reproductive system to lifespan extension in Caenorhabditis elegans. PLoS Genet 5:e1000639
Lee, Seung-Jae; Kenyon, Cynthia (2009) Regulation of the longevity response to temperature by thermosensory neurons in Caenorhabditis elegans. Curr Biol 19:715-22
Berman, Jennifer R; Kenyon, Cynthia (2006) Germ-cell loss extends C. elegans life span through regulation of DAF-16 by kri-1 and lipophilic-hormone signaling. Cell 124:1055-68
Arantes-Oliveira, Nuno; Berman, Jennifer R; Kenyon, Cynthia (2003) Healthy animals with extreme longevity. Science 302:611