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

项目摘要/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。可以在晚年的明显表现之前识别的生物老化的指标 条件，以及相应地作为未来健康和寿命的预测指标，可以促进这一努力。AS 在本RFA中强调的是弹性，定义为有机体对物理环境做出充分反应的能力 挑战，可能会提供一个这样的机会。因此，本提案的目标是制定和验证 一系列疾病不可知的物理挑战，以使评估小鼠的复原力。为此，在 具体目标1我们将确定哪些体能挑战最能显示和之间的弹性差异 在年轻的、中年的和老年的小鼠中。具体地说，我们将评估麻醉的急性反应， 4个月龄、12个月龄和20个月龄小鼠的化疗、手术和脱水。在……里面 具体目标2，使用在具体目标1中被认为是最佳的身体挑战，我们将确定 哪个中年小鼠的基线恢复力使用区分措施纵向预测健康寿命 梅奥诊所的身体、新陈代谢、心血管和免疫功能，以及加州大学的寿命 密歇根州。鉴于相当多的证据表明mTOR信号异常和衰老细胞积累 衰老的介体，在特定的目标3我们将确定雷帕霉素和靶向清除的程度 P16INK4a阳性衰老细胞的数量会影响老年小鼠对物理挑战的恢复能力。我们预计会有一个 实验室小鼠的临床相关弹性测量的标准化组合将提供一种新的 框架，以测试创新和潜在的变革性干预措施，以促进健康老龄化。在……里面 对于人类来说，慢性病和虚弱等症状的出现可能会反映出一种不归路。 另一方面，生命早期的韧性受损可能最终会成为治疗的机会 与衰老相关的分子和细胞损伤的进展可以减弱，如果不能逆转的话。

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.