Despite spectacular progress in many areas of molecular biology in recent years the fundamental question of how the rate of aging is controlled has remained quite mysterious. We wish to ask how the rate of aging is determined in the nematode C. elegans, using genetic and molecular approaches. C. elegans can exist in two alternative developmental states that have different life spans. One is the normal vegetative form, which ages rapidly. The other is the dauer, an alternative larval form induced by starvation and dauer pheromone, which is sealed off from the environment and very long lived. It has generally been assumed that he dauer lives longer simply because it is metabolically inert. However, our results with temperature-sensitive daf-2 mutants, which enter the dauer state at high temperature, suggest an alternative interpretation. We have discovered that daf-2(e1370) mutants live much longer than wild-type even at low temperature, at which other dauer phenotypes are not expressed. They look like non-dauer animals, and, unlike that dauer, they eat, move actively and produce progeny. The simplest interpretation of this observation is that in daf-2(e1370) mutants, the longevity phenotype has been activated independently of other dauer phenotypes. If this is true, it means there is a longevity program latent in the dauer that has the potential to lengthen its life span dramatically. Normally its is activated in dauers, but if triggered, it can operate in non-dauer as well. Like any regulated process, such as yeast mating type, sex determination, or cell-cycle control, this regulated extension of life span should be accessible to genetic analysis. C. elegans is probably the best multicellular organisms in which to dissect the regulation of life span genetically, because of its short life span and other genetic advantages. In addition, analysis of basic cellular processes, such as pattern formation, cell death, and signal transduction pathways, has shown that the basic cellular processes, such as pattern formation, cell death, and signal transduction pathways, has shown that the mechanisms that underlie cell growth and differentiation in C. elegans are highly conserved. Thus research on the regulation of aging in C. elegans is very likely to yield findings of general significance. We will use established genetic and molecular approaches to learn how aging is regulated in C. elegans. 1. We will identify additional genes that regulate life span by using two powerful and rapid methods to isolate mutants that live longer than the wild type. 2. Using standard epistasis tests, we will place our new mutations, as well as known mutations that affect dauer formation, into a regulatory pathway for the control of life span. 3. We will initiate a molecular analysis of daf-2 as well as genes we identify that specifically affect life span.
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