C. elegans is a powerful model for discovering mechanisms that influence aging. In C. elegans a reduction in the number of germline stem cells (GSCs) increases lifespan and stress resistance through a pathway that is distinct from those related to nutrient availability and growth signals, and may be conserved. The GSC longevity pathway may preserve reproductive capacity during adversity, and we speculate that it might also defend against stress associated with excess somatic production of proteins and lipids that would otherwise be committed to reproduction. The GSC pathway involves changes in lipid metabolism, autophagy, and proteasome activity. It is mediated through complex inter-organ signaling networks, and requires the longevity factor DAF-16/FoxO acting in the intestine (liver, fat, pancreas counterpart). Much remains to be learned about how this signaling works, and how the GSC longevity pathway increases lifespan and stress resistance. An understanding of the GSC pathway is of high impact and broad significance for human health because it provides 1) a novel window into tissue non-autonomous regulation of longevity assurance mechanisms, and 2) an example of how a germ or stem cell population communicates its status to """"""""niche"""""""" tissues that sustain it. Our unpublished results indicate that the GSC longevity pathway regulates the conserved stress defense and longevity factor SKN-1/Nrf in the intestine and that SKN-1 is required for the resulting increases in both lifespan and stress resistance. SKN-1 provides a highly advantageous opportunity to probe GSC pathway regulation through screening, and to determine how this pathway promotes longevity and fitness. This project will employ RNA interference (RNAi) screening for genes involved in its regulation of SKN-1 to elucidate GSC pathway regulatory mechanisms. It will also investigate our model that the GSC pathway involves two """"""""new"""""""" SKN-1 functions we have identified that may be important under conditions of secretory stress: proteostasis maintenance and regulation of lipid metabolism. Finally, the project will employ RNAseq expression profiling to identify genes and processes that are regulated by SKN-1 in response to GSC absence. This exploratory two-year project will make possible a number of exciting future studies, including investigating possible functional interactions among SKN-1, DAF-16, and other transcription factors involved in the GSC pathway, determining how SKN-1-regulated genes contribute to metabolic and biological processes that are modulated in response to GSC absence, and elucidating mechanisms through which the GSC pathway acts across and within tissues to regulate SKN-1 and other factors. The results are likely to be widely applicable to understanding processes that modulate longevity or coordinate communications among tissues that influence aging of the organism.

Public Health Relevance

Genetics-based studies of the nematode C. elegans and other invertebrates have identified mechanisms that profoundly influence aging, and in many cases seem to be evolutionarily conserved. We propose an exploratory effort to investigate how C. elegans lifespan and stress resistance are increased when its reproductive stem cells are absent, by focusing on a conserved stress defense and longevity-promoting regulator (SKN-1/Nrf). The findings are likely to be widely applicable to understanding processes that modulate longevity or coordinate communications among tissues that influence aging, and to understanding how a germ or stem cell population communicates its status to other tissues that sustain it.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Murthy, Mahadev
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Joslin Diabetes Center
United States
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Steinbaugh, Michael J; Narasimhan, Sri Devi; Robida-Stubbs, Stacey et al. (2015) Lipid-mediated regulation of SKN-1/Nrf in response to germ cell absence. Elife 4:
Blackwell, T Keith; Steinbaugh, Michael J; Hourihan, John M et al. (2015) SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans. Free Radic Biol Med 88:290-301