TESTING THE ABILITY OF NOVEL ASSAYS OF RESILIENCE TO PREDICT LIFESPAN

摘要 将动物研究转化为人类研究的主要限制之一是，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 该RFA的目标是确定是否可以找到小鼠恢复力的测量值， 长寿和健康。弹性被定义为"生物体应对身体挑战的能力 或压力并恢复体内平衡"，即，适应力不仅仅是衡量一群动物的能力， 才能在有毒的压力下生存根据RFA的目标，我们假设，增加对各种疾病的适应能力， 在中年的压力可以用来预测的能力，操纵，以增加小鼠的寿命。 在这个应用程序中。我们将测试一组七项弹性指标，这些指标基于：（1）相对 简单、廉价和非侵入性的，并且可以在整个动物体内进行;（2）测量 一系列生理学领域;（3）整合的测定，即，对压力的反应包括一系列 维持体内平衡的途径和/或多个器官;以及（4）可以潜在地转化为 人类这些测定预测哪些操作将增加寿命的能力将在本研究中进行测试。 的目标。1：开发体内试验，测量小鼠的恢复力。我们将开发七个 恢复力测定，以最大限度地提高其灵敏度，以检测小鼠恢复力的变化。这些分析将 测量对以下的反应：（1）外源蛋白/抗原，（2）跑步机耐力运动能力，（3）恢复 麻醉、（4）角叉菜胶诱导的爪炎症、（5）热应激、（6）缺氧和（7）束缚 应力第2章：确定我们的韧性指标是否能预测小鼠队列的寿命 据知它能延长寿命我们将在一组小鼠中测量恢复力，这些小鼠已经被证明是 平均寿命和最长寿命都有显著增长。例如，饮食限制和生长激素 (GH)缺乏症（艾姆斯侏儒小鼠）以及用化合物治疗的小鼠， 测试计划（ITP）已显示出稳健地增加寿命：雷帕霉素，阿卡波糖和17-α-雌二醇。3.到 确定恢复力测试是否能预测单个小鼠的寿命和健康寿命增加。使用 一组遗传多样性小鼠（多样性外杂交），我们将确定Aim 2中的测定是否预测了 一个动物能活多久使用生命末期的整体病理学作为衡量每只动物健康的指标，我们 也将决定韧性是否能预测健康状况。

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.