NEUROBEHAVIORAL AND IMMUNOLOGICAL MARKERS OF AGING

本申请满足RFA AG-91-17中概述的目标， “衰老生物标志物的发展”，来自国家研究所， 衰老 当前研究者根据既往生物标志物开展的工作 老年RFA的研究表明，涉及运动的神经行为标志物， 感觉运动，学习和最近的记忆功能显示可靠的 作为年龄的函数的变化模式。 此外，与年龄有关的 对这些能力的选定测试的改变被发现是延迟的 在长期饮食限制的小鼠中， 这表明，这些措施是敏感的变化率， 生物老化 目前的申请建议继续研究 的有效性，可靠性和一般性测试的认知和 感觉运动过程作为生物老化的标志。 此外该 研究人员将同时考虑生物化学措施， 氧化应激/损伤作为潜在的生物标志物。 两大行为 范式将用于评估认知能力（i）一个地方 涉及空间辨别的学习记忆任务 以及（ii）具有多个组件的延迟反转任务，包括 概念容量、工作记忆和长期保持 能力将使用（i）加速旋转杆范例进行评估 和（ii）解决运动和反射能力的动力电池。 将推断神经和外周组织中的氧化应激/损伤 通过（i）氧化还原对的还原/氧化形式的比率， NADH/NAD+、NADPH/NADP+和GSH（还原型谷胱甘肽）/GSSG（氧化型 谷胱甘肽），（ii）蛋白质氧化修饰成羰基 衍生物，（iii）膜蛋白-SH基团的损失，和（iv） 谷氨酰胺合成酶、葡萄糖-6-磷酸 脱氢酶和甘油醛-3-P脱氢酶。 烷烃析出 将被用作体内水平的非侵入性指标， 氧化应激 神经行为和生化指标的有效性 生物标志物将通过（i）确定它们对生物标志物的敏感性来测试。 长期饮食限制的影响，一个假设可以改变 （二）确定其预测个体的能力; 寿命或功能老化的差异。 的一般性的 将通过种内基因型检测神经行为生物标志物 比较以及涉及测试大鼠的跨物种比较 在相同的行为协议下，在直接与博士合作。 大卫奥尔顿和同事（约翰霍普金斯大学系。心理学）。 生物化学和神经行为实验的结果将导致 生物年龄的非侵入性测量的发展， 与人类应用程序直接平行。

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.