NEUROBEHAVIORAL AND IMMUNOLOGICAL MARKERS OF AGING

衰老的神经行为和免疫标志物

• 批准号: 2049854
• 负责人: HARBANS LAL
• 金额: $ 21.87万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2049854
• 关键词: aging; antioxidants; behavior test; biomarker; cognition; dietary control; discrimination learning; enzyme activity; genetic strain; genotype; glucose 6 phosphate dehydrogenase; glutamate ammonia ligase; glutathione peroxidase; glutathione reductase; glyceraldehyde 3 phosphate dehydrogenase; laboratory mouse; longevity; longitudinal animal study; memory; motivation; neuropsychological tests; neuropsychology; nutrition of aging; nutrition related tag; oxidative stress; psychomotor function; sensorimotor system; sensory mechanism; species difference; statistics /biometry

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.

该申请旨在解决RFA AG-91-17中概述的目标 美国国家研究所的“衰老生物标志物的发展” 老化。 现任研究人员在以前的生物标志物下的工作 衰老的RFA表明涉及运动的神经行为标记， 感觉运动，学习和最近的记忆功能显示可靠 变化模式随着年龄的函数。 另外，与年龄有关 发现这些能力的选定测试的变化被发现延迟 在经过长期饮食限制的小鼠中， 表明这些措施对变化的速度敏感 生物衰老。 当前的申请建议继续研究 认知和测试的有效性，可靠性和一般性 感觉运动过程是生物衰老的标记。 另外， 调查人员将同时考虑生化措施 氧化应激/损伤作为潜在的生物标志物。 两个主要行为 范式将用于评估认知能力（i） 学习任务，涉及空间歧视的学习和记忆 （ii）延迟的逆转任务，其中有许多组件，包括 概念能力，工作记忆和长期保留感觉运动 将使用（i）加速的rotorod范式评估容量 （ii）电池电池可寻求运动和反射能力。 将推断出神经和周围组织中的氧化应激/损伤 通过（i）氧化还原夫妇的还原/氧化形式的比率 NADH/NAD+，NADPH/NADP+和GSH（还原谷胱甘肽）/GSSG（氧化 谷胱甘肽），（ii）将蛋白质氧化为羰基 衍生物，（iii）膜蛋白-SH组的损失，（iv） 酶谷氨酰胺合成酶，葡萄糖-6-磷酸的活性 脱氢酶和甘油醛-3-P脱氢酶。 烷烃呼气 将用作体内水平的非侵入性指标 氧化应激。 神经行为和生化的有效性 生物标志物将通过（i）确定其敏感性来测试 长期饮食限制的影响，该程序假定会改变 衰老率和（ii）确定他们预测个人的能力 寿命或功能衰老的差异。 一般性 神经行为生物标志物将通过物种内基因型进行测试 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，与博士直接合作 戴维·奥尔顿（David Olton）和同事（约翰·霍普金斯大学（Johns Hopkins Univ）心理学系）。 生化和神经行为实验的结果将领导 开发生物年龄的非侵入性测量 直接与人类应用相似。