The general aim of our research program has been to investigate the endocrine mechanisms responsible for the age-related decline in tissue protein synthesis and function with age. The specific focus of this application is to determine the impact of age-related decreases in growth hormone and insulin-like growth factor-1 (IGF-1) on brain aging. Our working hypothesis is that 1) a decrease in the amplitude of growth hormone secretion and plasma IGF-1 results in rarefaction of cerebral vasculature and a decline in vascular IGF-1, 2) a decline in vascular IGF-1 (and possibly other neurotropic factors) secreted into surrounding tissues results in the appearance of age-related tissue pathophysiology including a reduction in protein synthesis, c-fos expression, protein kinase C and tyrosine kinase activity. These changes can be reversed by administration of GRF to increase growth hormone and IGF-1. This hypothesis will be tested by: 1) assessing age-related changes in local cerebral blood flow and c-fos expression in vivo. Basal and IGF-1 induced tyrosine kinase, protein kinase C and C-fos activity will be assessed using a brain slice preparation. 2) Determining whether chronic pulsatile administration of GRF which increases both growth hormone and IGF-1 ameliorates the age-related changes in local cerebral blood flow, protein kinase C, c-fos expression and protein synthesis. A subset of animals will be used to assess the direct effects of growth hormone administration to insure that the effects are specific to growth hormone and IGF-1. 3) Assessing whether growth hormone regulates IGF-1 and type 1 IGF receptor mRNA, growth hormone and type 1 IGF receptors and IGF-1 secretion in isolated vasculature. In addition, the effects of chronic administration of GRF on vascular response to growth hormone and IGF-1 will be assessed by measuring c-fos, tyrosine kinase and protein kinase C activity in isolated vasculature. These studies are designed to address the novel concept that loss of functional vasculature with age and its associated metabolic nutritional and neurotrophic support leads to diminished synaptogenesis, functional and morphological changes in brain and in some cases, cell loss. Results of these studies have important implications for the mechanisms of brain aging and the etiology of vascular dementia.
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