The broad goal of this proposed research is to investigate how Wnt signaling regulates mammalian aging. Wnt's are a family of secreted proteins that are important in cell-cell communication during embryogenesis and for maintaining adult stem cell niches and overall tissue/organ homeostasis. We recently reported that the mammalian aging regulator klotho acts as a secreted Wnt antagonist and that in the absence of klotho, in vivo Wnt signaling is augmented. We further observed that chronic up-regulation of Wnt signaling contributes to the accelerated senescence of proliferating progenitor cells and the depletion of stem cells within multiple tissues and organs ofthe klotho deficient mouse. These results suggest that Wnt signaling might play an important role in regulating mammalian aging. We have recently further explored other potential endogenous regulators of Wnt signaling and have discovered that insulin stimulation can strongly inhibit Wnt signaling. Since insulin signaling plays an important role in regulating aging in a wide range of species, we speculate that the intersection of the Wnt and insulin pathways may be important in the overall regulation of aging. Similarly, since Wnt signaling is essential for stem cell self renewal and tissue/organ maintenance and since insulin functions as a major regulator of energy metabolism, we believe these observations might provide a mechanism by which metabolism might directly impact tissue maintenance and ultimately mammalian aging. In this proposed study, we will test this hypothesis using both diet-induced and genetic models of metabolic disorders. We will investigate the effects of obesity and its associated high circulating insulin concentrations on adult stem cell self renewal capacity and overall function. We will also investigate the molecular mechanisms by which insulin inhibits Wnt signaling, as well as how Wnt signaling rnay feedback to regulate glucose metabolism. Overall this proposed study investigates the mechanisms of mammalian aging from two novel view points: How energy metabolism intersects with stem cell function and organ homeostasis and how Wnt signaling and insulin signaling might intersect in regulating aging. It is our belief that this study will provide novel insights in our understanding of both metabolic regulation as well as on the mechanisms underlying mammalian aging.
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