The primary goal of this program project is to investigate the effects of age related decreases in growth hormone (GH), and insulin-like growth factor-1 on brain microvasculature and brain aging. Aging is accompanied by decline in high amplitude, pulsatile GH secretion and a concomitant reduction in plasma IGF-1. Decreases in these hormones are responsible, in part, for the age-related reduction in protein synthetic capacity and subsequent decline in the function of many tissues. Although IGF-1 mRNA and receptors are present in both brain and brain microvasculature, the function of IGF-1 in the brain, the regulation of brain vasculature by GH and/or IGF-1, and the interaction between age-related changes in vasculature and brain aging are poorly understood. Preliminary data are presented that demonstrate a close relationship and interdependence between the age-related decline in GH and IGF-1 and microvasculature and brain aging. Our working hypothesis is that plasma IGF-1 participates in the maintenance of vascular tissue which, in turn, secretes IGF-1 and other neurotropic factors thereby influencing surrounding neurons and glia. The decrease in GH and subsequent decrease in plasma IGF-1 with age result in a rarefaction of cerebral vasculature, a decline in vascular IGF-1 and a subsequent reduction in brain blood flow, c-fos expression, protein kinase C activity, and a loss of synapses and neurons: Administration of GRF to increase plasma GH and IGF-1 will prevent rarefaction of cerebral vasculature and ameliorate age-related changes in brain structure and function. Project 1 (Dr. Philip Hutchins, PI) will assess age-related changes in the cerebral microvasculature using a cortical 'window' technique and determine the dependence of the vasculature on GH and IGF-1. Project 2 (Dr. William E. Sonntag, PI) will assess age-related changes in brain blood flow, c-fos expression, tyrosine kinase and protein kinase C activity and the effects of GH and IGF-1 on these processes. Project 3 (Dr. Judy Brunso-Bechtold, PI) will address age-related neural and vascular changes in central auditory and sensory/motor structures. Specifically neuron, glia, capillary density and size, synaptic density and length and neurotransmitter distribution will be assessed in aging animals and in animals after restoration of GH pulses by chronic pulsatile infusion of GRF. A central Animal/Statistical/Administration CORE is proposed that links the three projects. This program project will provide valuable information on the interactions between the endocrine, vascular and central nervous systems which may contribute to vascular dementia and increased susceptibility to diseases commonly observed in the elderly.
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