This application addresses the goals outlined in RFA AG-91-17, """"""""Development of Biomarkers of Aging"""""""" from the National Institute on Aging. Work by the current investigators under the previous biomarkers of aging RFA suggests that neurobehavioral markers involving locomotor, sensorimotor, learning, and recent memory functions show reliable patterns of change as a function of age. In addition, age-related changes in selected tests for those capacities were found to be delayed in mice which had been subjected to long-term dietary restriction, suggesting that those measures were sensitive to changes in the rate of biological aging. The current application proposes to continue studies of the validity, reliability, and generality of tests for cognitive and sensorimotor processes as markers of biological aging. In addition, the investigators will concurrently consider biochemical measures of oxidative stress/damage as potential biomarkers. Two main behavioral paradigms will be used for assessment of cognitive capacities (i) a place learning task involving learning and memory for spatial discrimination and (ii) a delayed reversal task with a number of components, including conceptual capacity, working memory, and long-term retention Sensorimotor capacities will be assessed using (i) an accelerating rotorod paradigm and (ii) a motor battery addressing locomotor and reflexive capacities. Oxidative stress/damage in neural and peripheral tissues will be inferred by (i) ratios of the reduced/oxidized form of the redox couples such as NADH/NAD+, NADPH/NADP+ and GSH (reduced glutathione)/GSSG (oxidized glutathione), (ii) oxidative modification of proteins into carbonyl derivatives, (iii) loss of membrane protein -SH groups, and (iv) activities of the enzymes glutamine synthetase, glucose-6-phosphate dehydrogenase and glyceraldehyde-3-P dehydrogenase. Alkane exhalation will be used as a non invasive indicator of the in vivo level of oxidative stress. The validity of the neurobehavioral and biochemical biomarkers will be tested by (i) determining their sensitivity to the effects of long term diet restriction, a procedure assumed to alter the rate of aging and by (ii) determining their ability to predict individual differences in longevity or functional aging. The generality of the neurobehavioral biomarkers will be tested by within-species genotype comparisons as well as cross-species comparisons involving rats tested under the same behavioral protocols, in direct collaboration with Dr. David Olton and co-workers (Johns Hopkins Univ. Dept. of Psychology). The results of the biochemical and neurobehavioral experiments will lead to the development of non-invasive measurements of biological age with direct parallels to human applications.
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