Optimizing resilience assays for biology of aging research in mice

建议书摘要 寿命和健康寿命的评估仍然是记录衰老研究有效性的基石。 然而，人们越来越认识到，将啮齿动物安置在常规的、无端的条件下， 而不是暴露在自由生活的人类通常遇到的相同种类的压力源下， 我们对如何将这些策略最有效地转化为人类的理解。如本文件中所定义 RFA弹性是生物体对身体挑战或压力做出反应并恢复到 动态平衡。生理韧性随着年龄的增长而下降，这可能是导致和可能导致 与衰老相关的疾病。因此，早年或中年的弹性可能预示着未来的健康寿命和 长寿。因此，开发了一套简单、短期的检测方法来表征啮齿类动物的弹性 可以通过实现快速、廉价和全面的策略来诊断老化研究，从而使老龄化研究发生革命性变化 干预效果，对未来结果有可能的预测价值。因此，我们提出了一系列 简单、多样的挑战和分析，包括择期手术、放射、饥饿和感染模型 描述啮齿动物的韧性，目的是预测未来的结果。我们假设 超凡的韧性是健康衰老和长寿所必需的，该检测方法经过优化以检测变异 在韧性方面可以预测长期的老龄化结果。在目标1中，我们将建立和优化电池 功能测试，以区分CB6F1雄性和雌性小鼠的生理弹性随年龄的变化。 这一目标的目的是用良好的- 已建立的人类同源基因(辐射、饥饿、手术和感染)和直接反应 在4、12和20mo龄的小鼠身上进行检测(即体重、体温等)。我们将考虑实施 成功地观察到年龄对应激源的敏感性，并在反应中增加组内变异性 随着年龄的增长，这将证实区分好的、中等的和差的应答者作为 在目标2中，我们将测定12个月龄时的复原力预测能力 未来的健康跨越多个领域(认知、心血管、神经肌肉、代谢)以及 长寿。在目标3中，我们将确定药物干预是否具有显着性二态 对衰老结果的影响在生理弹性方面也有相似的性别差异。这一目标将试图 验证针对调整寿命的干预措施的优化弹性测试的能力，方法是关注以下两个方面 在生存方面具有显著性别差异的药物策略。为此，16岁的男性和女性 给小鼠注射偏爱雄性的17α-雌二醇和偏爱雌性的胰岛素样生长因子-1R单抗4个月， 并确定是否可以使用我们的优化电池检测到特定性别的弹性改善 化验。开发、改进和验证易于执行的弹性分析不仅有助于 解决老龄研究中的一个重要差距，但将对临床前老龄研究的进展情况产生重大影响 在未来进行的。

Proposal Summary Evaluation of lifespan and healthspan remain a cornerstone of documenting efficacy in aging research. However, it is becoming increasingly appreciated that housing rodents in conventional, unprovoked conditions, rather than exposed to the same variety of stressors normally encountered by free-living humans, has limited our understanding of how these strategies can be most effectively translated to humans. As defined in this RFA resilience is the ability in which an organism can respond to a physical challenge or stress and return to homeostasis. Physiologic resilience declines with age and can contribute to, and may underlie the onset of aging-related conditions. Thus, resilience in early or mid-life may be predictive of future healthspan and longevity. Thus, development of a simple, short-term battery of assays to characterize resilience in rodents could revolutionize aging research by enabling a rapid, inexpensive and comprehensive strategy to diagnose intervention efficacy, with possible prediction value for future outcomes. Therefore, we propose a battery of simple, diverse challenges and assays to include elective surgery, radiation, starvation, and an infection model to characterize resilience in rodents with the goal of predicting future outcomes. We hypothesize that exceptional resilience is requisite to healthy aging and longevity, and that assays optimized to detect variation in resilience can be prognostic of long-term aging outcomes. In Aim 1, we will establish and optimize a battery of functional tests to distinguish changes in physiologic resilience with aging in CB6F1 male and female mice. The goal of this aim is to calibrate both the application and detection of responses to stressors with well- established human homologues (radiation, starvation, surgery, and infection) and straight-forward response assays (i.e. body weight, temperature, etc) in mice at 4, 12, and 20 mo of age. We will consider implementation successful with observed age sensitivity to the stressor and increasing intra-group variability in the response with advancing age, which will confirm the potential for discriminating good, average and poor responders as a predictor of outcomes in Aim 2. In Aim 2, we will determine the ability of resilience at 12 mo of age to predict future healthspan across multiple domains (cognitive, cardiovascular, neuromuscular, metabolic) as well as longevity. In Aim 3, we will determine if pharmacologic interventions with demonstrated sexually-dimorphic effects on aging outcomes confer similar sex differences in physiologic resilience. This Aim will attempt to validate the ability of optimized tests of resilience to interventions that modulate lifespan by focusing on two pharmacologic strategies with striking sex differences on survival. To that end, 16 mo old male and female mice for 4 mo with 17α-estradiol, which preferentially favors males, and IGF-1R mAb, which favors females, and determine if sex-specific improvements in resilience can be detected using our optimized battery of assays. Development, refinement, and validation of easily performed assays of resilience will not only help address an important gap in aging research, but will have a major impact on how pre-clinical aging studies are conducted in the future.