A sex difference approach to evaluating resilience as a predictor of healthspan in mice

项目摘要 人口老龄化已成为全球人类健康的头号威胁， 预期寿命正在迅速上升，因为老龄化是几乎所有死亡、残疾和 晚年生活质量的下降。改善这一趋势的希望在于发展 增强和延长健康的治疗。评价有前途的化合物的一个主要限制是， 衰老抑制特性是在小鼠中进行寿命研究所需的时间，主要的临床前研究 用于生物医学研究的动物模型。类似地，一旦化合物准备好用于人体测试， 完成临床试验的时间也将成为瓶颈。为了加快这一领域的进展 那么，开发一组短期试验将是非常宝贵的， 早期到中年，可以预测干预是否会延长小鼠的健康寿命。的能力 众所周知，从急性身体挑战或压力中恢复的生物体随着年龄的增长而衰退。如果我们 将恢复力定义为衡量生物体恢复的能力和速度的定量指标。 身体压力或挑战后的体内平衡，那么延长生命和健康的干预措施通常会增强 resilience.拟议研究的目标是制定一个标准化的挑战或挑战小组 及其附带的恢复指标，这些指标将提供有关假定的 在生命早期至中期进行的健康扩展干预。最重要的假设是 建议的研究是，弹性测定可以单独或组合开发，预测未来的生活- 和/或健康跨度。我们建议评估我们的总体假设，有目的地侧重于弹性 通过执行以下特定目标（SA），进行具有翻译潜力的测定。SA 1将优化弹性 测定方案，每个方案由急性物理挑战和相关的恢复指标组成， 使用挑战的年龄和严重程度。SA 2将确定是否在特定条件下优化了弹性测定， 目标1可以确定已知的寿命或健康寿命延长治疗的影响。三个这样的治疗将是 与未处理的对照组相比。它们是：（a）饮食限制。这可以被认为是积极的 控制为了提供信息，我们的弹性测定应该预测两性的寿命更长;（B）雷帕霉素，我们的 弹性测定应该预测两性的寿命更长，但对女性的影响更大;和（c）17-α-雌二醇。 我们的恢复力测试应该只预测男性的寿命更长。SA 3将评估大多数 在特定目标2中跨小鼠基因型鉴定了成功的恢复力测定。因为人类是如此 遗传和环境多样性，小鼠试验的通用性应最大限度地提高， 可能不同的小鼠基因型可用于评估aim 2中开发的检测方法是否 对原始测试基因型来说是特异质的，或者是我们希望用于人体试验的稳健的。

Project Summary Aging of the human population has become the number one threat to human health globally as life expectancy is rising rapidly and because aging underlies nearly all major causes of death, disability, and degradation of the quality of later life. Hope for amelioration of this trend lies with the development of treatments that enhance and extend health. A major limitation on evaluating promising compounds for their senescence-inhibiting properties is the time it takes to perform lifespan studies in mice, the main preclinical animal model employed in biomedical research. Similarly, once compounds are ready for human testing, the time it takes to complete clinical trials will also become a bottleneck. In order to speed progress in the field then, it would be invaluable to develop a panel of short-term assays that could be administered to mice in early- to mid-life that would predict whether or not an intervention will extend healthspan in mice. The ability of an organism to recover from acute physical challenges or stresses is well-known to decline with age. If we define resilience as a quantitative metric which gauges the ability and speed of an organism to return to homeostasis after physical stress or challenge, then life- and health-extending interventions generally enhance resilience. The goal of the proposed research is to develop a standardized challenge or panel of challenges and their accompanying recovery metrics that will be informative about the healthspan impact of putative health-extending interventions when administered in early-to-mid life. The overarching hypothesis of the proposed research is that resilience assays can be developed that singly, or in combination, predict future life- and/or health-span. We propose to evaluate our overarching hypothesis purposely focusing on resilience assays with translational potential by performing the following specific aims (SAs). SA 1 will optimize resilience assay protocols, each consisting of an acute physical challenge and associated recovery metrics as to the best age and severity of challenge to use. SA 2 will determine whether the resilience assays optimized in specific aim 1 can identify the impact of known life- or health-span extension treatments. Three such treatments will be compared to untreated controls. These are: (a) dietary restriction (DR). This can be thought of as a positive control. To be informative, our resilience assays should predict longer life in both sexes; (b) rapamycin, our resilience assays should predict longer life in both sexes, but a greater effect in females; and (c) 17-α-estradiol. Our resilience assays should predict longer life in males only. SA 3 will evaluate the robustness of the most successful resilience assays identified in specific aim 2 across mouse genotypes. Because humans are so genetically and environmentally diverse, the generality of mouse assays should be maximized to the extent possible. Diverse mouse genotypes are available to access whether the assays developed in aim 2 are idiosyncratic to the original test genotype or robust as we would want for human trials.