TESTING THE ABILITY OF NOVEL ASSAYS OF RESILIENCE TO PREDICT LIFESPAN

摘要 将研究从动物转移到人类的主要限制之一是，寿命不是 合理或可行的终点，用于确定手法是否延缓人体衰老。因此， 这种RFA的目标是确定是否可以在小鼠中找到作为增加的替代物的弹性测量 长寿健寿。复原力的定义是有机体对身体挑战的反应能力 或压力和回归动态平衡“，即韧性不是简单地衡量一群动物的能力 才能在有毒的压力下生存。基于本RFA的目标，我们假设增强对各种 中年的压力可以用来预测手法延长小鼠寿命的能力。 在此应用程序中。我们将测试一组七种弹性指标，其基础是：(1)相对 简单、廉价和非侵入性的，可以在整个动物体内进行；(2)测量 一系列生理领域；(3)综合性的分析，即对压力的反应涉及一系列 维持动态平衡的途径和/或多个器官；以及(4)可能被翻译成 人类。这些分析预测哪些操作将延长寿命的能力将在 遵循目标。1：开发将在小鼠身上测量弹性的体内试验。我们将开发七个 弹性测试，以最大限度地提高检测小鼠弹性变化的灵敏度。这些化验结果将 测量反应：(1)外来蛋白质/抗原，(2)跑步机耐力运动能力，(3)恢复 麻醉后，(4)角叉菜胶引起的爪部炎症，(5)热应激，(6)缺氧，(7)束缚 压力。2：为了确定我们的恢复力测量是否可以预测小鼠队列的寿命 已知能延长寿命。我们将测量一群小鼠的韧性，这些小鼠已经被证明 平均寿命和最长寿命都有强劲的增长。例如，饮食限制和生长激素 (GH)缺乏(Ames侏儒小鼠)以及用化合物治疗的小鼠，NIA资助的干预 测试计划显示可以显著延长寿命：雷帕霉素、阿卡波糖和17-α-雌二醇。3.至 确定弹性测试是否可以预测单个小鼠的寿命和健康寿命的增加。vbl.使用 一群遗传多样性的小鼠(多样性外杂交)，我们将确定目标2中的检测是否可以预测 动物会活得很久。使用生命末期的全球病理学作为衡量每种动物健康的指标，我们 还将确定恢复力是否可以预测健康状况。

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.