Longevity is influenced by genetic pathways and environmental factors. The goals of this project are to (a) elucidate mechanisms by which some genes enhance longevity and (b) identify environmental and physiological factors that can slow aging. These studies focus on aging in the nematode, Caenorhabditis elegans, which is one of the premier organisms for studying aging. The current popularity of C. elegans as a focus for studies of aging comes from its short lifespan (2-3 weeks), ease of cultivation and amenability to genetic manipulation.? ? Insulin-like signaling pathways are important regulators of longevity in several species, from worms to flies to mice, and could also affect human longevity. In C. elegans, lifespan can be increased dramatically by mutations that disrupt signaling downstream of the insulin receptor-like (IR) protein, DAF-2. In addition to regulating lifespan, DAF-2/IR signaling regulates larval development and adult stress resistance and metabolism. Extended lifespan in mutants with disrupted insulin signaling results from activation of DAF-16, a FOXO transcription factor which is a conserved target of insulin-like pathways in many animals. When active, DAF-16/FOXO controls expression of an array of genes that promote longevity and stress resistance. Thus, FOXO transcription factors may be evolutionarily conserved regulators of longevity. ? ? Current work aims to define how FOXO transcription factors affect longevity and to identify FOXO-interacting pathways. First, we have described how DAF-2/insulin receptor signaling within a variety of cell types can promote normal lifespan. In particular, DAF-2 function within intestinal cells is a major contributor to longevity, but DAF-2 signaling within neurons can also contribute to a normal lifespan. These findings led to the hypothesis that DAF-2 signaling regulates an endocrine-like lifespan-control signal which is produced by many cell types. In contrast, there are other functions of DAF-2 that are regulated primarily by its function within intestinal cells. Furthermore, we have also reported that activated DAF-16/FOXO appears to be required in many cells in order to extend lifespan. This finding led us to revise the original hypothesis to include the possibility that DAF-2 can regulate DAF-16/FOXO within the same cell, but that there must also be cell-cell signaling pathways responsible for coordinating DAF-16/FOXO activity throughout the body. ? ? We are working to rapidly identify compounds with prolongevity activity in C. elegans. Lead compounds that clear this screen can be further studied for their effects on aging in mammals, which requires more time-consuming and costly procedures. Current work is focused on plant polyphenols and related compounds. Blueberries contain a high abundance of polyphenolic compounds. In vitro, these compounds possess high antioxidant activity. We have found that treatment with blueberry polyphenols can significantly prolong C. elegans lifespan and delay the accumulation of aging-related damage. The bioactive compounds co-fractionate with a proanthocyanidin-enriched fraction, but not with other antioxidant polyphenols. Genetic analysis revealed that treatment with blueberry polyphenols did not lead to induction of stress resistance pathways. Our current model is that blueberry polyphenols protected cells from intrinsic stress that leads to cellular decline during aging. ? ? We are studying normal aging in C. elegans to identify how aging causes functional and structural declines in tissues, particularly muscles. Current work investigates the basis for aging-related declines of the pharynx muscles. The pharynx is the worms feeding organ and is composed of 20 muscle cells. We have found that aging primarily affects the ability of pharynx muscles to respond to neuronal stimulation, and probably does not significantly affect neuronal function. In addition, we have found that muscle contraction is probably a major contributor to functional declines in this organ during aging. Both genetic and longitudinal approaches are being used to define specific factors responsible for pharynx functional decline during aging. The results of these studies may provide new avenues for treating muscle deterioration in human aging.
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