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

项目总结/摘要 针对衰老基本机制的治疗干预正在寻求从根本上改变 公共卫生生物老化的指标，可以确定之前，明显表现出晚年 健康状况，并同时作为未来健康和寿命的预测因素，可以促进这一努力。作为 在这个RFA中强调，弹性，定义为生物体充分应对物理环境的能力。 挑战，可能会提供这样的机会。因此，本提案的目标是制定和验证一个 一系列疾病不可知的身体挑战，以评估小鼠的弹性。为此目的进行 具体目标1我们将确定哪些物理挑战最能揭示和之间的弹性差异 在年轻、中年和老年小鼠体内。具体来说，我们将评估麻醉的急性反应， 对4个月大、12个月大和20个月大的小鼠队列进行化疗、手术和脱水。在 具体目标2，使用具体目标1中认为最佳的物理挑战，我们将确定 中年小鼠的基线恢复力纵向预测健康寿命， 在马约诊所进行的身体、代谢、心血管和免疫功能的研究，以及在密歇根大学进行的寿命研究。 密歇根鉴于有相当多的证据表明，异常mTOR信号传导和衰老细胞积累， 老化介质，在具体目标3，我们将确定雷帕霉素和靶向清除的程度 p16 INK 4a阳性衰老细胞的减少影响老年小鼠对物理挑战的恢复力。我们预计， 一组标准化的临床相关实验室小鼠恢复力的测量将提供一个新的 该框架旨在测试创新和潜在的变革性干预措施，以促进健康老龄化。在 对于人类来说，慢性疾病和虚弱等综合症的出现可能反映了一个不可逆转的点。 另一方面，生命早期受损的恢复力最终可能会成为一个治疗机会， 其可以减弱（如果不能逆转的话）衰老相关的分子和细胞损伤的进展。

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.