Physical resilience is a predictor of healthy aging in mice

身体恢复能力是小鼠健康衰老的预测因素

• 批准号: 9418968
• 负责人: Warren C LADIGES
• 金额: $ 31.78万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9418968
• 关键词: Address; Adverse effects; Age; Aging; Aging-Related Process; Animals; Biological; Clinical; Clinical Research; Cyclophosphamide; Developed Countries; Developing Countries; Development; Diabetes Mellitus; Dose; Effectiveness of Interventions; Goals; Health; Health Status; Heart Diseases; Hematopoietic System; Histologic; Human; Individual; Institution; Insulin Resistance; Long-Term Effects; Longevity; Malignant Neoplasms; Measurement; Measures; Memory Loss; Mus; Organ; Organism; Patients; Pharmaceutical Preparations; Physiological; Research; Rheumatoid Arthritis; Risk Factors; Sirolimus; Sleep; Sleep Deprivation; Sleep Fragmentations; Sleep disturbances; Stress; Stress Tests; System; Testing; Therapeutic; Tissues; age related; anti aging; base; chemotherapeutic agent; chemotherapy; effectiveness measure; experience; frailty; healthy aging; indexing; middle age; natural hypothermia; normal aging; pre-clinical; resilience; response; stressor; tool

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.

身体恢复能力是小鼠健康衰老的预测因素 抽象的 身体弹性是有机体应对身体压力的能力，可以用以下方法来衡量 各种类型的压力测试。恢复力的丧失比衰弱的发生要早得多。因此， 失去弹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，以便了解患者的整体健康状况 动物。因此，更有可能的是一系列压力测试，而不是单一的包罗万象的压力测试， 将会提供更多信息。理想的一组测试应具有足够的响应动态范围，以允许 将易于区分的群体中的个体表征为有弹性或无弹性。我们有 选择寒冷、睡眠不足和化疗药物环磷酰胺三种压力源， 根据重复特征和翻译相关性进行调查。人们产生不耐受 随着年龄的增长，对低温的敏感性也会增加。对寒冷的反应机制是 多因素的。睡眠不足是发达国家的一个主要健康问题，并且与 年龄增长，是胰岛素抵抗、糖尿病和记忆丧失的危险因素。大约三分之一 发达国家的人们在一生中经历过某种类型的化疗，环磷酰胺 是测试弹性的优秀代表性化疗剂，因为它广泛用于 患有多种疾病的患者，包括癌症和类风湿性关节炎。它针对几个不同的系统 但最具体的是造血系统。该提案的假设是身体压力 寒冷、睡眠不足和环磷酰胺测试组将测量恢复能力并预测健康状况 小鼠的衰老。为了解决这一假设，我们制定了三个具体目标。目标 1 将验证 弹性参数。中年小鼠将面临寒冷、睡眠不足和 环磷酰胺，并通过生理学和组织学测量进行评估，以确定 强度和执行压力测试组的顺序。目标 2 将调查年龄依赖性 弹力。不同年龄的小鼠将面临寒冷、睡眠剥夺和环磷酰胺的挑战， 通过生理和组织学测量进行评估，以便建立剂量反应的基线 与生物年龄相符。目标 3 将确定压力小组衡量弹性的能力 抗衰老药物的终点。为此，我们选择了雷帕霉素，因为它在 延长小鼠的寿命并增强其健康寿命，也是因为我们在该药物方面拥有丰富的经验 小鼠衰老研究。该提案的结果将是发展复原力作为转化老龄化的手段 签名提供了一个额外的工具来验证临床前小鼠研究产生的药物反应， 临床抗衰老试验。