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