During the past decade, it has become clear that the rate of aging, like many other processes in biology, is subject to regulation. In many animals, including mammals, longevity is regulated by a conserved insulin- and IGF-l-like signaling pathway. This longevity system was discovered in the genetically-tractable organism C. elegans, and a great deal about it has been learned by studying this animal. In C. elegans, DAF-2, an insulin/IGF-l-like receptor, activates a conserved signal transduction pathway that inhibits longevity, at least in part, by inhibiting the activity of the transcription factor DAF-16. In mutants defective in this signaling pathway, DAF-16 accumulates in the nucleus and coordinates expression of a battery of diverse downstream genes that together produce dramatic extensions of lifespan. This study addresses key, unsolved questions about this signaling pathway. Sensory neurons regulate the DAF-2 pathway, possibly in response to environmental cues, and this study tests the hypothesis that sensory neurons influence lifespan by controlling the production or release of specific insulin-like peptides. The C. elegans heat-shock transcription factor, HSF-1, which regulates the highly-conserved heat-shock response, acts with DAF-16 to regulate the expression of genes required for youthfulness and longevity. This study will determine how HSF-1 activity is regulated and how it functions in this system. Finally, a large number of genes with unknown functions act in this system to influence longevity. This study will better define the biochemical roles that these genes play in the aging process. Together these studies may ultimately define new therapeutic strategies for combating age-related disease and increasing the quality of old age.
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