Role of GH/IGF1 signaling pathway on pro-longevity miRNAs

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The long-goal of this proposal is to identify circulating micro RNA (miRNAs) as potential juvenile protective factors that mediate the effects of somatotropic signaling during postnatal development on healthy aging. With the growing population of elderly people, there is growing incidence of age-related diseases including metabolic syndrome, atherosclerotic disease, insulin resistance and diabetes mellitus. Several studies with mice and rats indicated that obesity causes insulin resistance and has negative effects on longevity. Calorie restriction decreases the volume of fat, improves insulin sensitivity and extends longevity. However, our studies with long-living Ames dwarf (df/df) mice indicated that these growth hormone deficient animals have altered function of adipose tissue promoting healthy phenotype regardless of predisposition to obesity during aging. We propose the general hypothesis hypothesis that alterations in the levels of circulating miRNA species secreted by adipose tissue-derived MSCs link hormonal signaling during development with control of aging. In the proposed studies, we will investigate the effects of growth hormone (GH) and adiponectin on the levels of putative pro-longevity miRNA in circulation and insulin target organs. To test our hypothesis we propose four specific aims: 1. Determine the mechanism by which GH/IGF-1 and adiponectin signaling pathways regulate expression of putative pro-longevity miRNAs in Ames dwarf and normal mice. 2. Determine to what extent MSCs contribute to the release of circulating putative pro-longevity miRNAs in response to GH/IGF-1 or adiponectin. Investigate to what extent exosomes contained in the serum of df/df mice can infiltrate target cells in vitro to reduce production of pro-inflammatory cytokines and adipokines.