How the rate of aging is determined is a fundamental problem in biology. Recently, tremendous progress has been made by identifying and characterizing genes that influence the aging of nematode C. elegans. This organism has a very rapid rate of aging and lives just a little over two weeks, making it very easy for investigators to identify and characterize mutations affecting aging. Studies in a number of labs, including ours, have shown that a pathway that is similar to the vertebrate insulin and IGF-1 signaling pathways controls the rate of aging in C. elegans. When a homolog of the insulin/IGF-1 receptor, DAF-2, is partially disabled, the animals live twice as long as normal, remaining active and healthy when normal worms are decrepit and still (nursing-home appearance). Since many biological processes in C. elegans have been shown to be conserved with higher organisms, studies of this pathway may ultimately allow us to devise strategies for improving the quality of old age in humans. My lab originally discovered that daf-2 mutations increase lifespan. During this funding period, we have shown that DAF-2 acts in signaling cells, which, in turn, must produce a second signal that directly controls the rate of aging. In addition, we have identified and cloned a transcription factor whose activity is required to extend the lifespans of daf-2 mutants. Here we propose to learn which cells in the animal require the activity of this transcription factor, and whether its activity can be sufficient to extend the lifespans of otherwise normal animals. Many mysteries remain. How DAF-2 influences the production of the secondary signal(s), the identity of this signal(s), the signal transduction pathway that must operate in target tissues, and the mechanism by which this pathway controls aging are all unknown. To find the missing genes, we carried out a large-scale mutant screen and isolated twenty new long- lived mutants. During this funding period, we will begin to learn what genes these mutations affect, and how these genes influence the aging process. We will also assemble a set of fluorescent molecular biomarkers of aging that can be observed in living animals. These markers will revolutionize the study of aging because they will allow us to describe the aging process more accurately in normal and long- lived animals, to identify new aging mutants extremely rapidly, and also to analyze mutants with accelerated aging. Understanding this pathway in detail will ultimately answer the two most important questions in the aging field: how the aging process itself takes place, and how it can be regulated by endocrine signaling.
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