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: 10166752
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10166752
• 关键词: Address; Age; Aging; Animals; Biological; Clinical; Clinical Research; Cyclophosphamide; Developed 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; Process; Research; Rheumatoid Arthritis; Risk Factors; Sirolimus; 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; healthspan; healthy aging; indexing; middle age; natural hypothermia; normal aging; pre-clinical; resilience; response; side effect; 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因子 摘要 身体弹性是生物体对身体压力做出反应的能力，可以用 各种压力测试。恢复力的丧失比脆弱的发展要早得多。因此，在本发明中， 恢复力的丧失可能导致与年龄相关的虚弱。在衡量整体复原力时， 涉及多个组织、器官和活动的信息是期望的，以便告知患者的总体健康状况。 那个禽兽因此，更有可能的是一系列压力测试，而不是一个单一的包罗万象的测试， 会更有信息量。一组理想的测试应该有足够的动态范围， 在容易区分的群体中将个体表征为有弹性或无弹性。我们有 选择了三种压力源，寒冷，睡眠剥夺和化疗药物环磷酰胺， 根据重复的特点以及翻译关联性进行研究。人们会对 随着年龄的增长，对低温的敏感性增加。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， 随着年龄的增长，是胰岛素抵抗、糖尿病和记忆力丧失的危险因素。约三分之一 发达国家的人在一生中会经历某种类型的化疗， 是测试恢复力的极好的代表性化疗剂，因为它广泛用于 包括癌症和类风湿性关节炎在内的各种疾病的患者。它针对几个不同的系统 尤其是造血系统这个提议的假设是， 寒冷，睡眠剥夺和环磷酰胺的测试小组将测量恢复力并预测健康 衰老的老鼠针对这一假设，制定了三个具体目标。目标1将验证 弹性参数中年小鼠将受到寒冷、睡眠剥夺和 环磷酰胺，并用生理学和组织学测量进行评估，以建立 强度和施用应激测试板的顺序。目标2将研究年龄依赖性 resilience.将用寒冷、睡眠剥夺和环磷酰胺攻击不同年龄的小鼠， 通过生理学和组织学测量进行评估，以建立剂量反应的基线 与生物年龄相符的基因目标3将确定应力小组作为一个 抗衰老药物的终点。为此，我们选择了雷帕霉素，因为它是有据可查的， 延长小鼠的寿命和提高健康寿命，也因为我们有这种药物的经验， 小鼠衰老研究。这一建议的结果将是发展的弹性作为一个翻译老化 签名提供了一个额外的工具来验证药物反应，从临床前小鼠研究中产生， 临床抗衰老试验