Senescence is a multifactorial process, which appears to be associated with increases in both oxidative and inflammatory events. The ability to slow or reverse changes associated with brain aging by dietary supplementation will be investigated with a focus on these two processes. Following an initial survey of a broad range of agents, melatonin has been selected for detailed study. Changes in gene expression following treatment of aged mice with melatonin will be evaluated using array technology in combination with Northern blotting. Investigation of those genes associated with inflammatory or pro-oxidant events will be emphasized. The cytosolic pathways leading to genomic modulation will be sought. Levels of proteins potentially affected by altered mRNA levels will be quantitated using ELISA and Western assays. The ability of melatonin to restore integrity of mitochondrial functioning and retard age-related mitochondrial DNA deletion will be evaluated. Immunohistochemical identification of specific peptides from fixed tissue sections will allow a more precise localization of any changes observed. Arrest or reversal of trends associated with age will be evaluated by comparison of patterns of mRNA and proteins from dosed mice with those from younger animals. Parallel studies using behavioral endpoints will reveal whether molecular changes detected, are reflected by altered cognition or motor strength. The degree of consonance between biological and behavioral changes may imply a causal relation. Results will contribute to development of a rational strategy for delaying progression of brain aging. This is also likely to be relevant to slowing the onset of, and reducing the incidence of, several neurodegenerative diseases where age is a major co-factor. ? ?
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