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. These findings led to the hypothesis that DAF-2 signaling regulates longevity and development through an endocrine-like output. Using microarray-based analysis of gene expression, we compared global gene expression profiles in long-lived animals lacking insulin signaling and two strains with insulin-signaling restored to specific tissues. This analysis revealed specific transcriptional targets of the insulin pathway that are regulated in response to tissue-restricted insulin signaling. Current work is focused on elucidating the signaling pathways that couple with insulin signaling to regulate these targets. ? ? We are also working to 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. Previous work focused on polyphenolic proanthocyanins from blueberries. We also recently completed analysis of a panel of stilbene molecules differing in methoxylation at the R groups. Stilbenes are also polyphenolic compounds found in a variety of plants. In contrast to the prolongevity effects of blueberry proanthocyanins, the methoxylated stilbenes were toxic to adult C. elegans. Methoxylated stilbenes also inhibited germline tumor growth in animals carrying a mutation resulting in uncontrolled mitotic proliferation of germcells. This is the first systematic demonstration that stilbene methoxylation can increase bioactivity in a whole animal. Future work will focus on identifying the biological targets of methoxylated stilbenes in C. elegans.? ? These studies are complemented by structural studies of aging-related changes in the C. elegans pharynx, a neuromuscular organ responsible for food ingestion and mechanical disruption. Using computer-based image classification, we examined patterns of structural change in the pharynx during aging. The analysis revealed the existence of several stable morphology states that were associated with characteristic points of the C. elegans lifespan. Particular ages were associated with transitions between sequential morphology states. We hypothesize that the stability of aging morphology states reflects the activity of cellular homeostatic mechanisms coping with aging-related ceellular changes. The identification of these stable aging morphology states introduces a novel biomarker of aging that may be useful for studying the mechanisms leading to aging-related declines.
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