NEUROBEHAVIORAL AND IMMUNOLOGICAL MARKERS OF AGING

本申请涉及RFA AG-91-17中概述的目标， 《衰老生物标记物的发展》，来自美国国立卫生研究院 衰老。现任调查人员在以前的生物标志物下的工作 衰老的RFA表明，神经行为标记物涉及运动， 感觉运动、学习和最近的记忆功能显示可靠 随年龄变化的模式。此外，与年龄有关的 对这些容量的选定测试的更改被发现被推迟 在长期饮食限制的小鼠中， 这表明这些措施对增长率的变化很敏感 生物老化。目前的申请建议继续学习 认知能力测验的效度、信度和通用性 感觉运动过程作为生物老化的标志。此外， 调查人员将同时考虑生物化学指标 氧化应激/损伤作为潜在的生物标志物。两种主要行为 认知能力的评估将使用范式(I)一个地点 空间辨别涉及学习和记忆的学习任务 和(2)具有若干组成部分的延迟反转任务，包括 概念容量、工作记忆与长时记忆感觉运动 将使用(I)加速旋转棒范例来评估能力 和(Ii)马达电池，用于解决运动和反射能力。 神经和周围组织中的氧化应激/损伤将被推断 通过(I)氧化还原对的还原/氧化形式的比率，例如 NADH/NAD+、NADPH/NADP+和GSH/GSSG(氧化) 谷胱甘肽)，(Ii)蛋白质氧化修饰为羰基 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-磷酸的活性 脱氢酶和甘油醛-3-P脱氢酶。烷烃呼出 将作为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 生物标志物将通过以下方式进行测试：(I)确定其对 长期饮食限制的影响，这一程序被认为可以改变 老龄化速度和(Ii)确定他们预测个人的能力 在寿命或功能老化方面的差异。这一概念的普遍性 神经行为生物标记物将通过种内基因型进行测试 比较以及跨物种比较，涉及被测试的老鼠 在相同的行为协议下，与Dr直接合作。 大卫·奥尔顿和同事(约翰·霍普金斯大学部门心理学)。 生化和神经行为实验的结果将导致 对生物年龄的非侵入性测量的发展 直接与人类应用程序相似。

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.