Aging and Resiliency in Mice: Optimizing Assessment Protocols and Testing Interventions

小鼠的衰老和恢复能力：优化评估方案和测试干预措施

• 批准号: 9173625
• 负责人: Nathan K LeBrasseur
• 金额: $ 41万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9173625
• 关键词: Acute; Affect; Age; Age-Months; Aging; Anesthesia procedures; Animal Model; Attenuated; Biological Aging; Biology of Aging; Body Weight; CDKN2A gene; Cardiovascular system; Cell Aging; Cells; Chronic Disease; Clinic; Cytotoxic agent; Dehydration; Disease; Elderly; Evaluation; Excision; Exhibits; FRAP1 gene; Future; Genetic; Glucose; Health; Homeostasis; Human; Immune; Innovative Therapy; Intervention; Laboratory mice; Left Ventricular Mass; Life; Longevity; Maintenance; Measures; Mediating; Mediator of activation protein; Metabolic; Michigan; Molecular; Mus; Operative Surgical Procedures; Organism; Osmolalities; Outcome; Physical assessment; Physiological; Plasma; Protocols documentation; Public Health; Recovery; Resources; Signal Transduction; Sirolimus; Stress; Surrogate Markers; Syndrome; System; T-Lymphocyte Subsets; Testing; Therapeutic; Therapeutic Intervention; Time; Transgenes; Universities; Work; age group; age related; aging population; blood glucose regulation; chemotherapy; clinically relevant; cohort; disability; exercise capacity; experience; frailty; healthy aging; immune function; indexing; innovation; middle age; mortality; peer; resilience; response; senescence

PROJECT SUMMARY/ABSTRACT Therapeutic interventions that target fundamental mechanisms of aging are being sought to radically transform public health. Indicators of biological aging that can be identified prior to overt manifestations of late-life conditions, and concomitantly serve as predictors of future health and longevity, could facilitate this effort. As highlighted in this RFA, resilience, defined as the ability of an organism to adequately respond to physical challenges, may offer one such opportunity. Thus, the objective of this proposal is to develop and validate a battery of disease-agnostic physical challenges to enable the evaluation of resiliency in mice. To this end, in Specific Aim 1 we will determine which physical challenges best reveal differences in resilience between and within younger, middle-aged, and older mice. Specifically, we will assess acute responses to anesthesia, chemotherapy, surgery, and dehydration in cohorts of 4-month-old, 12-month-old, and 20-month-old mice. In Specific Aim 2, using the physical challenges deemed optimal in Specific Aim 1, we will determine the extent to which baseline resilience of middle-aged mice longitudinally predicts healthspan using discriminating measures of physical, metabolic, cardiovascular, and immune function at Mayo Clinic, and lifespan at the University of Michigan. Given the considerable evidence that aberrant mTOR signaling and senescent cell accumulation are mediators of aging, in Specific Aim 3 we will determine the extent to which rapamycin and targeted clearance of p16INK4a-positive senescent cells affect the resilience of older mice to physical challenges. We expect that a standardized battery of clinically relevant measures of resilience in laboratory mice will provide a new framework in which to test innovative and potentially transformative interventions to promote healthy aging. In humans, the emergence of chronic diseases and syndromes such as frailty may reflect a point of no return. Compromised resilience earlier in life, on the other hand, may ultimately serve as a therapeutic opportunity in which the progression of aging-related molecular and cellular damage can be attenuated, if not reversed.

项目摘要/摘要 靶向衰老基本机制的治疗干预措施正在寻求从根本上转化 公共卫生。可以在晚期明显表现之前鉴定的生物衰老指标 条件，同时可以作为未来健康和寿命的预测因素，可以促进这一努力。作为 在此RFA中突出显示的弹性，被定义为有机体充分反应物理的能力 挑战可能会提供一个这样的机会。因此，该提案的目的是开发和验证 疾病敏锐的身体挑战可以评估小鼠的弹性。为此， 具体目的1我们将确定哪些物理挑战最能揭示与和 在年轻，中年和年长的老鼠中。具体而言，我们将评估对麻醉的急性反应， 4个月大，12个月大的和20个月大的小鼠的同类中的化​​学疗法，手术和脱水。在 特定目标2，利用特定目标1中认为最佳的身体挑战，我们将确定 哪种中年小鼠的基线弹性纵向使用歧视措施来预测健康状态 Mayo诊所的身体，代谢，心血管和免疫功能以及大学的寿命 密歇根州。鉴于有很多证据表明异常的MTOR信号传导和衰老细胞积累是 衰老的介体，在特定目的3中，我们将确定雷帕霉素的靶向清除程度 P16INK4A阳性的衰变细胞影响老鼠对身体挑战的弹性。我们期望 实验室小鼠中临床相关的弹性措施的标准化电池将提供新的 在其中测试创新和潜在的变革性干预措施以促进健康衰老的框架。在 人类，慢性疾病和综合症（例如脆弱）的出现可能反映出没有回报的点。 另一方面，生命早期的韧性妥协最终可能是一种治疗机会 如果不逆转，与衰老相关的分子和细胞损伤的进展可能会减弱。