In 1999, we discovered that removing C. elegans' germ cells extends the lifespan of the whole animal. This life extension requires the presence of the somatic reproductive tissues, so, essentially, an empty gonad extends life. This pathway, which may be conserved evolutionarily, is fascinating biologically, as it appears to coordinate two key life-history traits, aging and reproduction. This system involves conserved proteins that act in new, poorly understood, tissue-to-tissue signaling pathways: Reproductive signals are sent to the intestine (C. elegans' entire endoderm), which in turn processes these signals to activate life-extending transcription factors. Learning how this longevity pathway operates could ultimately suggest new entry points for improving human health and longevity. Here, we build upon our previous findings to address key unanswered questions about this pathway. First, our studies have shown that there are two signaling pathways from the reproductive system. The first, a steroid-hormone pathway, allows the somatic reproductive tissues to communicate with the intestine. However, we find that loss of the germ cells activates several essential life-extending events independently of the somatic reproductive tissues. In this study, we will determine what signals are produced by the germ line itself to influence lifespan. Second, we find that when the germ line is gone, the level of reactive oxygen species (ROS) increases in the intestine. This ROS is required for life extension, at least in part by activating the SKN-1/Nrf2 antioxidant/xenobiotic response regulator. In this project, we will identify pathways that stimulat ROS production and SKN-1 activity in the intestine when the germ line is gone. Third, the life extension produced by germ line loss requires the conserved transcription factor DAF- 16/FOXO. This DAF-16-activation pathway is distinct from the pathway that activates DAF-16 in insulin/IGF-1 pathway mutants. In this study, we will learn how new DAF-16-activating proteins interact functionally and physically with one another. Together these studies will bring mechanistic insight to this fascinating life-extension system.

Public Health Relevance

This study delineates mechanisms by which reproductive signals can activate conserved life-extending proteins in the nematode C. elegans. Many conserved longevity pathways were first discovered in this animal, so these studies could identify new entry points for influencing human health and longevity.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Guo, Max
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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