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TESTING THE ABILITY OF NOVEL ASSAYS OF RESILIENCE TO PREDICT LIFESPAN

测试新的弹性分析方法预测寿命的能力

基本信息

批准号：
10165438
负责人：
ARLAN G. RICHARDSON
金额：
$ 30.54万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10165438
关键词：
Acarbose Affect Age-Months Aging Anesthesia procedures Animals Antigens Behavioral Biological Assay Biology of Aging Caenorhabditis elegans Carrageenan Clinical Trials Communities Data Death Records Disease Dwarfism Estradiol Female Funding Future Genetic Goals Growth Health Health Status Heat Stress Disorders Homeostasis Human Hypoxia Individual Inflammation Intervention Invertebrates Longevity Measures Mus Nutritional Organ Organism Pathologic Pathology Pathway interactions Pharmacology Physiological Positioning Attribute Proteins Recording of previous events Recovery Research Resources Rodent Series Sirolimus Stratification Stress Testing Time Translating Variant age related base cohort dietary restriction end of life endurance exercise exercise capacity experimental study genetic manipulation growth hormone deficiency healthspan in vivo intervention effect male middle age novel programs resilience response restraint restraint stress sex treadmill

项目摘要

ABSTRACT One of the primary limitations to translating studies from animals to humans is that lifespan is not a reasonable or feasible end-point to use in determining if a manipulation retards aging in humans. Therefore, the goal of this RFA is to determine if measures of resilience in mice can be found that are surrogates for increased longevity and healthspan. Resilience is defined as the “ability of an organism to respond to physical challenges or stresses and return to homeostasis”, i.e., resilience is not simply a measure of the ability of a cohort of animals to survive a toxic stress. Based on the goals of this RFA, we hypothesize that increased resilience to various stresses in mid-life can be used to predict the ability of a manipulation to increase the lifespan of mice. In this application. we will test a battery of seven measures of resilience based on; (1) assays that are relatively simple, inexpensive, and non-invasive and can be performed in whole animals in vivo; (2) assays that measure a range of physiological domains; (3) assays that are integrative, i.e., the response to the stress involves a series of pathways and/or multiple organs to maintain homeostasis; and (4) assays that can potentially be translated to humans. The ability of these assays to predict which manipulations will increase lifespan will be tested in the following aims. 1: To develop in vivo assays that will measure resilience in mice. We will develop seven assays of resilience to maximize their sensitivity to detect changes in resilience in mice. These assays will measure the response to: (1) a foreign protein/antigen, (2) treadmill endurance exercise capacity, (3) recovery from anesthesia, (4) carrageenan-induced inflammation in the paw, (5) heat stress, (6) hypoxia, and (7) restraint stress. 2: To determine whether our measures of resilience predict the longevity of cohorts of mice known to have increased longevity. We will measure resilience in cohorts of mice that have been shown to have a robust increase in both mean and maximum lifespan. For example, dietary restriction and growth hormone (GH) deficiency (Ames dwarf mice) as well as mice treated with compounds, which the NIA-funded Intervention Testing Program (ITP) has shown to robustly increase lifespan: rapamycin, acarbose, and 17-α-estradiol. 3. To determine if the tests of resilience predict increased longevity and healthspan in individual mice. Using a cohort of genetic diverse mice (diversity out cross), we will determine whether the assays in Aim 2 predict how long an animal will live. Using global pathology at the end of life as a measure of the health of each animal, we will also determine if resilience is predictive of health status.

抽象的将动物研究转化为人类的主要限制之一是寿命不是一个用于确定操作是否延缓人类衰老的合理或可行的终点。因此，本次 RFA 的目标是确定是否可以找到小鼠恢复力的测量方法来替代增加的恢复力长寿和健康寿命。复原力被定义为“有机体应对身体挑战的能力或压力并恢复稳态”，即复原力不仅仅是衡量一群动物的能力为了在有毒压力下生存。根据本次 RFA 的目标，我们假设增强了对各种问题的抵御能力中年时期的压力可用于预测某种操作延长小鼠寿命的能力。在这个应用程序中。我们将测试一系列由七项弹性指标组成的衡量标准： (1) 相对性分析简单、廉价、非侵入性，可以在整个动物体内进行； (2) 测量的测定一系列生理领域； (3) 综合分析，即对应激的反应涉及一系列维持体内平衡的途径和/或多器官； (4) 可能转化为的检测人类。这些分析预测哪些操作将延长寿命的能力将在以下项目中进行测试：以下目标。 1：开发测量小鼠恢复能力的体内测定方法。我们将开发七弹性测定，以最大限度地提高其检测小鼠弹性变化的灵敏度。这些测定将测量对以下因素的反应：(1) 外来蛋白质/抗原，(2) 跑步机耐力运动能力，(3) 恢复麻醉、(4) 角叉菜胶引起的爪子炎症、(5) 热应激、(6) 缺氧和 (7) 束缚压力。 2：确定我们的弹性测量是否可以预测小鼠群体的寿命已知可以延长寿命。我们将测量小鼠群体的恢复力，这些小鼠已被证明能够平均寿命和最长寿命都有强劲增长。例如，饮食限制和生长激素 (GH) 缺乏症（艾姆斯侏儒小鼠）以及接受 NIA 资助的干预措施的化合物治疗的小鼠测试计划 (ITP) 已证明可显着延长寿命：雷帕霉素、阿卡波糖和 17-α-雌二醇。 3. 到确定弹性测试是否可以预测个体小鼠的寿命和健康寿命的延长。使用一组遗传多样性小鼠（杂交多样性），我们将确定 Aim 2 中的测定是否可以预测动物能活多久。我们利用临终时的全球病理学来衡量每只动物的健康状况，还将确定复原力是否可以预测健康状况。