This application is a competing continuation of a Program Project entitled 'Growth Hormone & IGF-1 in CNS and Cerebrovascular Aging'. The project is based on several key findings indicating that the progressive decline in plasma growth hormone and IGF-1 throughout the lifespan not only has an important effect on aging of peripheral tissues but that decreases in the levels of these hormones contribute to a decline in cognitive function. We hypothesize that the age-related cognitive decline results from a loss of growth hormone/IGF-1 dependent factors and/or inability to compensate for such a loss. Our proposed continued investigation into the role of growth hormone and IGF-1 deficiencies on brain aging includes three projects supported by Administration and Animal Cores. Project 1 is based on previously published seminal findings and preliminary studies that plasma growth hormone and IGF-1 are key regulators of vascular density, vascular reactivity and blood flow and hypothesizes that deficiencies in growth hormone and IGF-1 result in a mismatch between blood flow and metabolic demand in specific brain regions. Project 2 focuses on the role of growth hormone/IGF-l in regulating cell turnover in the aging brain and will assess whether the growth hormone/IGF-1 axis is a critical regulator of the replacement of both neurons and glia, sand that deficiency of these hormones result in increased oxidative stress and inflammation resulting in functional decline and a decreased ability to prevent and repair damage in the CNS. Project 3 is based on our findings that subunit levels of NMDA and AMPA types of glutamate receptors decrease with age in the rodent hippocampus and that IGF-1 infusion into the lateral ventricles increases synaptic complexity. Proposed studies will investigate age-related changes in the synaptic distribution of NMDA and AMPA subunits and their association with brain levels of IGF-1. An extremely novel aspect of this application is that the projects will incorporate an animal model of adult-onset growth hormone deficiency. This model will permit us to evaluate the specific actions of growth hormone and IGF-1 apart from pathological or secondary age-related changes within the CNS. The proposed studies will address key questions of the relationship between endocrine and microvascular changes and the neural substrates that contribute to cognitive decline, vascular dementia and increased susceptibility to diseases commonly observed in the elderly, including Alzheimer's disease. ? ? ?
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