We propose to evaluate the hypothesis that deleterious effects of aging on several muscles and connective tissues result from decreases in levels of the somatomedins (SMs), a recently recognized family of insulin-like growth factors (IGF-I and IGF-II) that play a major biological role in mediating the anabolic actions of pituitary growth hormone (GH). Circulating levels of the SMs have been shown to decrease relatively late in the lifespan of both humans and rats. On the basis of tissue culture studies, the SMs are now believed to have substantial effects on contractile and connective tissues. We propose a molecular and cell biological study of effects of short- and long-term restoration of SM levels (by administration of GH, a GH-inducing agent such as clonidine, or rat IGF-II) on several target tissues including skeletal muscle, heart, aorta, and cartilage. Emphasis will be on changes in specific proteins (myosin isozymes and elastin) and proteoglycans. We will also study effects of aging on the control of GH secretion and will monitor the levels of both IGFs in the circulation. The central focus will be on short-term (2 weeks) and long-term (6 months) experiments on control of GH secretion and the effects of GH and a GH-inducer on secretion and actions of the somatomedins in barrier-protected SPF Fischer 344 rats 8, 16, and 24 months of age at the end of the experiments. There will be parallel experiments on effects of human IGF-I and rat IGF-II on isolated cells and tissues to provide basic information on the actions of these hormones. This project will make contributions to knowledge of actions of the somatomedins on several important target tissues, effects of aging on these actions (as well as on the secretion of SM), and the possibility of reversing or preventing the deleterious effects of aging on these tissues.
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