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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-5 (J3))
Program Officer
Mackiewicz, Miroslaw
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University of Oklahoma Health Sciences Center
Internal Medicine/Medicine
Schools of Medicine
Oklahoma City
United States
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Tucsek, Zsuzsanna; Toth, Peter; Sosnowska, Danuta et al. (2014) Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation, and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer's disease. J Gerontol A Biol Sci Med Sci 69:1212-26
Toth, Peter; Tarantini, Stefano; Tucsek, Zsuzsanna et al. (2014) Resveratrol treatment rescues neurovascular coupling in aged mice: role of improved cerebromicrovascular endothelial function and downregulation of NADPH oxidase. Am J Physiol Heart Circ Physiol 306:H299-308
Masser, Dustin R; Bixler, Georgina V; Brucklacher, Robert M et al. (2014) Hippocampal subregions exhibit both distinct and shared transcriptomic responses to aging and nonneurodegenerative cognitive decline. J Gerontol A Biol Sci Med Sci 69:1311-24
Sosnowska, Danuta; Richardson, Chris; Sonntag, William E et al. (2014) A heart that beats for 500 years: age-related changes in cardiac proteasome activity, oxidative protein damage and expression of heat shock proteins, inflammatory factors, and mitochondrial complexes in Arctica islandica, the longest-living noncolonial an J Gerontol A Biol Sci Med Sci 69:1448-61
Csiszar, Anna; Gautam, Tripti; Sosnowska, Danuta et al. (2014) Caloric restriction confers persistent anti-oxidative, pro-angiogenic, and anti-inflammatory effects and promotes anti-aging miRNA expression profile in cerebromicrovascular endothelial cells of aged rats. Am J Physiol Heart Circ Physiol 307:H292-306
Bailey-Downs, Lora C; Tucsek, Zsuzsanna; Toth, Peter et al. (2013) Aging exacerbates obesity-induced oxidative stress and inflammation in perivascular adipose tissue in mice: a paracrine mechanism contributing to vascular redox dysregulation and inflammation. J Gerontol A Biol Sci Med Sci 68:780-92
Warrington, Junie P; Ashpole, Nicole; Csiszar, Anna et al. (2013) Whole brain radiation-induced vascular cognitive impairment: mechanisms and implications. J Vasc Res 50:445-57
Ungvari, Zoltan; Csiszar, Anna; Sosnowska, Danuta et al. (2013) Testing predictions of the oxidative stress hypothesis of aging using a novel invertebrate model of longevity: the giant clam (Tridacna derasa). J Gerontol A Biol Sci Med Sci 68:359-67
Ungvari, Zoltan; Podlutsky, Andrej; Sosnowska, Danuta et al. (2013) Ionizing radiation promotes the acquisition of a senescence-associated secretory phenotype and impairs angiogenic capacity in cerebromicrovascular endothelial cells: role of increased DNA damage and decreased DNA repair capacity in microvascular radiosens J Gerontol A Biol Sci Med Sci 68:1443-57
Csiszar, Anna; Sosnowska, Danuta; Tucsek, Zsuzsanna et al. (2013) Circulating factors induced by caloric restriction in the nonhuman primate Macaca mulatta activate angiogenic processes in endothelial cells. J Gerontol A Biol Sci Med Sci 68:235-49

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