GROWTH HORMONE\ IGF-1 DEPENDENT REGULATION OF NEURONAL\GLIAL GENESIS IN AGING CNS

University Of Oklahoma Hlth Sciences Ctr, Oklahoma City OK

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Abstract

Cognitive abilities often decline during normal aging but the structural and functional changes that underlie[unreadable] such deficits and the mechanisms that regulate them are poorly understood. The numbers of neurons and[unreadable] connections in most regions of the aging brain remain essentially stable, but aging-related cognitive deficits[unreadable] could arise from changes in neuronal communication and from dysregulation of the dynamic replacement of[unreadable] neurons, glia and synapses. The effects of such changes may be subtle but significant under basal[unreadable] conditions, and also significantly compromise the ability of the aging brain to respond to, and recover from,[unreadable] potentially damaging challenges. Thus, clarifying the mechanisms of regulation of both neuronal and glial[unreadable] replacement in the adult brain is essential for understanding normal brain senescence and for assessing[unreadable] prospects and strategies for preventing or reversing aging-associated cognitive decline. These experiments[unreadable] will extend our ongoing investigation of adult hippocampal neurogenesis in order to clearly establish which of[unreadable] four critical aspects of regulation - proliferation, cell commitment, differentiation and survival - are influenced[unreadable] by aging and regulated by the growth hormone/insulin-like growth factor-l (GH/IGF-I) axis. In addition to the[unreadable] quantitative assessment of neurogenesis, experiments will assess the impact of aging-related changes in[unreadable] GH/IGF-I on oligodendrocyte turnover, since aging and the GH/IGF-I system appear to influence the genesis[unreadable] and maturation of glia and maintenance of myelin. In light of evidence that the GH/IGF-I axis interacts with[unreadable] oxidative stress pathways and inflammatory cytokines, both of which contribute to brain aging and injury, the[unreadable] relationship among aging, the GH/IGF-1 axis, and pro-inflammatory signals in regulating cell turnover will be[unreadable] examined. The experiments will investigate the effects of normal aging and a clinically relevant challenge,[unreadable] whole brain irradiation, testing for the first time whether radiation-induced deficits in neuro- and glial genesis[unreadable] are greater in older rats than in young adults and whether GH/IGF-I supplementation protects against agingrelated[unreadable] and radiation-induced changes in cell turnover. When completed, the proposed studies will provide[unreadable] the most complete assessment to date of the role of a major growth factor system, the GH/IGF-I axis, in[unreadable] mediating changes in the aging brain that are likely to contribute to normal cognitive decline and the greater[unreadable] susceptibility of the senescent brain to damage.