BACKGROUND The free radical theory of aging has significant relevance in a number of age-related neurological disorders. Too many free radicals create cellular pollution that shuts down energy levels. They have also been implicated in the loss of physiological functioning associated with the aging of post mitotic cells such as the brain. The activities of enzymatic antioxidative defenses decrease in rat brain may be possible causes of age-associated increase in oxidative damage to macromolecules. METHODS We determined whether DL-alpha-lipoic acid (100 mg/kg body weight/day), and L-carnitine (300 mg/kg body weight/day) together when administered for 30 days declines the rate of oxidative stress-mediated macromolecular damages such as lipid peroxidation (LPO), protein carbonyl (PCO) and DNA protein cross-links in different anatomic regions (cortex, striatum and hippocampus). The activities of antioxidant enzymes in programmed aging were evaluated in the cortex, striatum and hippocampus of young and aged rat brain regions. RESULTS Aged rats elicited a significant decline in the antioxidant status and increase in LPO, PCO and DNA protein cross-links as compared to young rats in all the 3 brain regions. The increase in LPO, PCO and DNA protein cross-links were (35.8%, 35.6%, 43.5%) in cortex, (32.5%, 40.3%, 29.8%) in striatum and (62.7%, 42.4%, 34.9%) in hippocampus, respectively, in aged rats as compared to young rats. Co-supplementation of carnitine and lipoic acid was found to be effective in reducing brain regional LPO, PCO and DNA protein cross-links and in increasing the activities of enzymatic antioxidants in aged rats to near normalcy. CONCLUSIONS The combination of l-carnitine and lipoic acid overcame the oxidative stress induced rate of lipid peroxidation, protein carbonyl formation, accumulation of DNA protein cross-links and deficits in antioxidant enzyme activities in various brain regions of aged rats.