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The hypothesis that age-associated impairment of cognitive and motor functions is due to oxidative molecular damage was tested in the mouse. In a blind study, senescent mice (aged 22 months) were subjected to a battery of behavioral tests for motor and cognitive functions and subsequently assayed for oxidative molecular damage as assessed by protein carbonyl concentration in different regions of the brain. The degree of age-related impairment in each mouse was determined by comparison to a reference group of young mice (aged 4 months) tested concurrently on the behavioral battery. The age-related loss of ability to perform a spatial swim maze task was found to be positively correlated with oxidative molecular damage in the cerebral cortex, whereas age-related loss of motor coordination was correlated with oxidative molecular damage within the cerebellum. These results support the view that oxidative stress is a causal factor in brain senescence. Furthermore, the findings suggest that age-related declines of cognitive and motor performance progress independently, and involve oxidative molecular damage within different regions of the brain.Age-related impairments of cognitive and motor capacity have been linked to a number of deleterious morphologic and functional changes involving different parts of the brain that are normally associated with such functions (1-4). However, the nature of the causal factors responsible for these deleterious changes is poorly understood. Oxidative damage was considered as a likely cause of age-associated brain dysfunction because the brain is believed to be particularly vulnerable to oxidative stress due to a relatively high rate of oxygen free radical generation without commensurate levels of antioxidative defenses (5-8). Indeed, there is a progressive increase in the steady-state concentration of oxidatively modified DNA and proteins in the brain during aging (9-12). This increase would appear to be region specific, as indicated by the variations in levels of protein oxidative damage within different areas of the brain in aged mice (13).In the current experiments, the hypothesis that regionspecific oxidative molecular damage in the brain is linked to the senescent loss of cognitive and motor functions was tested by using aged mice as a model system. The approach used was based upon the general observation that individuals of similar advanced chronological age frequently show varying degrees of cognitive and/or motor impairment, with some exhibiting little or no age-associated loss and others showing marked dysfunction (14). If the hypothesis were valid, then variations in the degree of cognitive or motor impairments within a group of old mice should be correlated with oxidative damage in appropriate regions of the brain. This prediction was tested by first screening individual aged mice for their degree of impairment on a behavioral test battery developed specifically for the measurement of age-impaired cognitive, locomotor, and motor coordination skills (15-18). Following...

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