Date Available


Year of Publication


Document Type



Arts and Sciences



First Advisor

D. Allan Butterfield


The studies presented in this dissertation were conducted with the objective ofgaining greater understanding into the mechanisms of successful aging, the role ofmitochondria dysfunction in traumatic brain injury, and also on the mechanisms ofimproved learning and cognitive function in the aging.Aging is usually characterized by impairments in physiological functionsincreasing its susceptibility to dementia and neurodegenerative disorders. In thisdissertation, the mechanisms of dementia-free aging were investigated. The use of anantioxidant fortified diet and a program of behavioral enrichment in the canine model ofhuman aging was shown to result in a significant decrease in the levels of oxidativestress. A proteomic analysis of these brains also demonstrated a significant decrease inthe oxidative modification of key brain proteins and an increase in the expression levelsof other key brain proteins associated with energy metabolism and antioxidant systemswhich correlated with improved learning and memory.We show that following TBI key mitochondrial-related proteins undergoextensive oxidative modification, possibly contributing to the severe loss ofmitochondrial energetics and neuronal cell death previously observed in experimentalTBI.Taken together, these findings support the role of oxidative stress in thepathophysiology of aging and age-related neurodegenerative disorders and in CNS injury.These studies also show that antioxidants and a program of behavioral enrichmentprovide protection against oxidative stress-mediated cognitive impairments.



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