Physical resilience is a predictor of healthy aging in mice

身体弹性是小鼠健康衰老的预测因子 摘要 身体复原力是生物体对身体压力做出反应的能力，可以用 各种类型的压力测试。韧性的丧失比脆弱的发展要早得多。因此， 丧失韧性可能会导致与年龄相关的虚弱。在衡量整体弹性时，综合反应 需要涉及多个组织、器官和活动，以便了解 这只动物。因此，更有可能的是，一系列压力测试，而不是单一的全面测试， 将会提供更多的信息。理想的测试电池应该在响应中有足够的动态范围，以允许 在容易区分的群体中，将一个人描述为有弹性或无弹性。我们有 选择了三个应激源，寒冷，睡眠剥夺和化疗药物环磷酰胺，以 根据重复和翻译关联性的特点进行调查。人们开始不能容忍 寒冷，随着年龄的增长，对低体温的敏感度增加。对寒冷的反应机制是 多因素。在发达国家，睡眠不足是一个主要的健康问题，与 年龄增加，是胰岛素抵抗、糖尿病和记忆力丧失的危险因素。大约三分之一的人 发达国家的人一生中会经历某种类型的化疗，而环磷酰胺 是测试复原力的极具代表性的化疗药物，因为它在 患者患有各种疾病，包括癌症和类风湿性关节炎。它的目标是几个不同的系统 但更具体地说，是造血系统。这项提议的假设是，身体压力 寒冷、睡眠剥夺和环磷酰胺测试小组将测量韧性并预测健康 小鼠的衰老。为了解决这一假设，已经制定了三个具体目标。AIM 1将验证 弹性参数。中年的小鼠将受到寒冷、睡眠不足和 环磷酰胺，并通过生理和组织学测量进行评估，以建立 强度和管理压力测试板的顺序。Aim 2将调查年龄相关性 恢复力。不同年龄的小鼠将受到寒冷、睡眠剥夺和环磷酰胺的挑战，以及 通过生理和组织学测量进行评估，以建立剂量反应的基线 这与生物年龄相一致。目标3将确定压力小组衡量弹性的能力 终点是一种抗衰老药物。为此，我们选择了雷帕霉素，因为它在 延长小鼠的寿命和增强健康寿命，也是因为我们在 小鼠衰老研究。这一提议的结果将是韧性作为一种转换衰老的发展 签名提供了一个额外的工具来验证药物反应，这些反应是从临床前小鼠研究中产生的 临床抗衰老试验。

Physical resilience is a predictor of healthy aging in mice Abstract Physical resilience is the ability of an organism to respond to physical stress, and can be measured with various types of stress tests. The loss of resilience occurs much earlier than the development of frailty. Thus, loss of resilience may result in age-related frailty. When measuring overall resilience, integrative responses involving multiple tissues, organs, and activities are desirable, so as to inform about the overall health status of the animal. Therefore, it is more likely that a battery of stress tests, rather than a single all-encompassing one, will be more informative. An ideal battery of tests should have enough dynamic range in the response to allow characterization of an individual in easily distinguishable groups as being resilient or non-resilient. We have selected three stressors, cold, sleep deprivation and the chemotherapeutic drug cyclophosphamide, to investigate based on features of duplication as well as translational relevance. People develop intolerance to cold with increased sensitivity to hypothermia with increasing age. The mechanisms of response to cold are multifactorial. Sleep deprivation is a major health concern in developed countries and is associated with increasing age, and is a risk factor for insulin resistance and diabetes and memory loss. About one third of people in developed countries experience some type of chemotherapy in their lifetime, and cyclophosphamide is an excellent representative chemotherapeutic agent to test resilience because it is used extensively in patients for a variety of conditions including cancer and rheumatoid arthritis. It targets several different systems but most specifically the hematopoietic system. The hypothesis of this proposal is that a physical stress test panel of cold, sleep deprivation and cyclophosphamide will measure resilience and predict healthy aging in mice. Three specific aims have been developed to address this hypothesis. Aim 1 will validate resilience parameters. Mice at middle age will be challenged with cold, sleep deprivation, and cyclophosphamide, and assessed with physiological and histological measurements in order to establish intensity and a sequence for administering the stress test panel. Aim 2 will investigate age-dependent resilience. Mice at different ages will be challenged with cold, sleep deprivation, and cyclophosphamide, and assessed with physiological and histological measurements in order to establish a base line for dose response that aligns with biological age. Aim 3 will determine the ability of the stress panel to measure resilience as an endpoint to an anti-aging drug. For this, we have selected rapamycin because it is well documented in extending lifespan and enhancing health span in mice, and also because we have experience with the drug in mouse aging studies. The result of this proposal will be the development of resilience as a translational aging signature providing an additional tool to validate drug responses, generated from preclinical mouse studies, for clinical anti-aging trials.