Metal Homeostasis and Aging

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DESCRIPTION (provided by applicant): Aging is the single largest risk factor for disease in developed countries. The ongoing demographic "aging" of the American population has greatly increased the proportion of the population at risk for socially and economically important age-related diseases including Parkinson's disease, Alzheimer's disease and adult cancers [1]. Discoveries made over the last twenty years on the genetic modifiers of lifespan in the nematode C. elegans have been vital as an impetus for much of the research conducted on mammalian aging and even human genetic studies. This has revealed that many genes, such as those encoding insulin signaling functions, influence normal longevity and also determine disease pathology. However, we still lack an overall understanding of how intracellular signaling pathways influence aging at a biochemical and metabolic level which suggests we should seek new ways of studying aging in model organisms. Aging is associated with changes in body composition and loss of various homeostatic systems. In a nematode model, we have observed a dramatic loss of metal homeostasis with age and have evidence that alterations in metal abundance modulate lifespan. Here we propose to understand the contribution of a loss of metal homeostasis (metallostasis) to aging. We will identify novel regulators of metallostasis and small molecules that maintain metallostasis, improve health and extend lifespan. PUBLIC HEALTH RELEVANCE: Aging is associated with changes in body composition and with a loss of ability by the body or an individual cell to seek and maintain internal balance of various essential factors. An example of such an age-related change is the accumulation of metals in various tissues. This loss of metal homeostasis (metallostasis) is also characteristic of a number of age-related diseases. We will test this idea in C. elegans where we can routinely manipulate aging genetically and pharmacologically. This study will lead to the identification of genes that modulate metallostasis and to small molecules that maintain metallostasis to extend healthy lifespan.