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.

身体弹性是小鼠健康衰老的预测指标 抽象的 身体弹性是生物体应对身体压力的能力，可以用 各种类型的压力测试。恢复能力的丧失比脆弱的发展要早得多。因此， 恢复能力的丧失可能导致与年龄有关的脆弱。在测量整体弹性时，综合响应 涉及多个组织，器官和活动是可取的，以告知 动物。因此，一系列的压力测试，而不是单个无所不能的测试，更有可能 会更有益。理想的测试电池在响应中应具有足够的动态范围，以允许 在易于区分的群体中，个体的表征是具有弹性或非弹性的。我们有 选择了三种压力源，冷，睡眠剥夺和化学治疗药物环磷酰胺 根据重复的特征以及翻译相关性进行调查。人们变得不容忍 随着年龄的增长，对体温过低的敏感性增加。对寒冷的反应机制是 多因素。睡眠剥夺是发达国家的主要健康问题，与 增加年龄，是胰岛素抵抗和糖尿病和记忆力丧失的危险因素。大约三分之一 发达国家的人一生中经历了某种类型的化学疗法和环磷酰胺 是测试弹性的出色代表化学治疗剂，因为它广泛用于 患者患有多种疾病，包括癌症和类风湿关节炎。它针对几个不同的系统 但最具体地说是造血系统。该提议的假设是身体压力 寒冷，睡眠剥夺和环磷酰胺的测试面板将测量弹性并预测健康 小鼠衰老。已经开发了三个特定的目标来解决这一假设。 AIM 1将验证 弹性参数。中年的小鼠将受到寒冷，睡眠剥夺和 环磷酰胺，并通过生理和组织学测量进行评估以建立 强度和用于管理应力测试面板的序列。 AIM 2将调查与年龄有关 弹力。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 用生理和组织学测量评估以建立剂量反应的基线 这与生物年龄保持一致。 AIM 3将确定应力面板测量弹性的能力 抗衰老药物的终点。为此，我们选择了雷帕霉素，因为它已被充分记录 延长寿命和改善小鼠的健康跨度，也是因为我们有药物的经验 小鼠老化研究。该提案的结果将是发展弹性作为转化衰老的发展 签名提供了一种额外的工具来验证临床前小鼠研究产生的药物反应，用于 临床抗衰老试验。