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缘无故的条件下，而不是 暴露在与自由生活的人类通常遇到的相同种类的压力之下，限制了我们的 了解如何将这些策略最有效地转化为人类。如本RFA中所定义 恢复力是有机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，早年或中年的韧性可能预示着未来的健康寿命和寿命。 因此，开发一种简单、短期的检测方法来表征啮齿动物的复原力可能会 通过启用快速、廉价且全面的策略来诊断老化，从而彻底改变老化研究 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。我们假设这一特殊情况 恢复力是健康衰老和长寿所必需的，该测试被优化以检测韧性的变化 可以预测长期老龄化的结果。在目标1中，我们将建立和优化一组功能 区分CB6F1雄鼠和雌鼠生理弹性随年龄变化的试验。的目标是 这一目的是为了校准对应激源的反应的应用和检测与已建立的人类 同系物(辐射、饥饿、手术和感染)和直接反应分析(即身体 体重、体温等)在4、12和20个月龄的小鼠。我们将认为实施是成功的 观察到年龄对应激源的敏感性以及随着年龄的增长反应中组内变异性的增加， 这将证实区分好的、一般的和差的应答者作为结果预测因子的可能性 在目标2.在目标2中，我们将确定在12个月龄时预测未来健康跨度的能力 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 确定有性二态影响的药物干预是否会对衰老结果产生影响 在生理弹性方面存在类似的性别差异。这一目标将试图验证优化的能力 通过重点研究两种药物策略来测试对调节寿命的干预措施的弹性 在存活率上存在显著的性别差异。为此，16只月龄雄性和雌性小鼠服用17α-雌二醇4个月， 优先偏爱男性的IGF-1R mAb和偏爱女性的IGF-1R mAb，并确定是否具有性别特异性 使用我们优化的检测电池可以检测到弹性的改善。开发、完善、 对易于执行的弹性分析的验证不仅有助于解决老龄化中的一个重要差距 但这将对未来如何进行临床前衰老研究产生重大影响。

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 contributes 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.