Lifespan regulation by the DAF-12 nuclear hormone receptor in C. elegans

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DESCRIPTION (provided by applicant): Several years ago, the Kenyon lab discovered that the reproductive tissues of C. elegans profoundly affect lifespan. This is intriguing, as the link between aging and reproduction is central to life history. When the germline is removed, lifespan is extended ~60%. Thus somehow the germline shortens lifespan. Conversely, the somatic reproductive tissues extend lifespan, because if they are removed in animals lacking a germline, no lifespan extension occurs. Recently, the Kenyon lab discovered that signaling from the reproductive system to the intestine, which is also the animal's adipose tissue, is required for lifespan extension. A lipophilic-hormone signaling pathway triggers the nuclear localization of DAF-16/FOXO, a lifespan-extending transcription factor, within the intestine. A second, yet undefined, pathway up-regulates a new, essential transcription factor in the intestine. The Kenyon lab has found that the somatic reproductive tissues are required for DAF-16 to activate some but not all of its target genes, and it has identified several genes that may be required for this somatic-gonad activity. Autophagy, microRNA processing, innate immunity and regulated proteolysis all appear to play a role in this lifespan-extending system, as do additional signaling proteins and transcription factors. During this funding period, the Kenyon lab will use genetics, laser microsurgery and molecular approaches to investigate how these and new genes act at the molecular level to execute and coordinate an extension in lifespan when the germline is removed. When the reproductive tissues are perturbed in long-lived insulin/IGF-1 -pathway mutants, the animals remain healthy and vigorous and live six times as long as normal. This spectacular lifespan extension provides a wonderful opportunity to address, using genetics and molecular biology, the question of how dramatic differences in lifespan can be produced. Are the same genes that are up-regulated in the long-lived insulin/IGF-1-pathway mutants further stimulated, or are new genes activated? How different species in nature evolved striking differences in lifespan is a profound and fundamental question. This study, which takes place within a single, genetically-tractable, species, provides a fantastic opportunity to identify mechanisms that can produce extreme differences in lifespan