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，与生命一样 预期寿命正在迅速上升，因为老龄化几乎是导致死亡、残疾和 晚年生活质量的下降。改善这一趋势的希望在于……的发展。 增强和延长健康的治疗。评价前景看好的化合物的一个主要限制是 衰老抑制特性是在小鼠身上进行寿命研究所需的时间，这是主要的临床前研究 生物医学研究中使用的动物模型。同样，一旦化合物准备好进行人体测试， 完成临床试验所需的时间也将成为瓶颈。为了加快这一领域的进展 然后，开发一组短期测试将是无价的，可以用在老鼠身上 这将预测干预是否会延长小鼠的健康寿命。的能力 众所周知，从剧烈的身体挑战或压力中恢复的有机体会随着年龄的增长而衰退。如果我们 将复原力定义为一种量化指标，用于衡量生物体重返 在身体压力或挑战后的动态平衡，那么延长生命和健康的干预措施通常会增强 恢复力。拟议研究的目标是制定一个标准化的挑战或挑战小组 以及随附的恢复指标，这些指标将提供有关假定的健康范围影响的信息 在生命早期到中期实施的健康延伸干预。最重要的假设是 拟议的研究是，可以开发出单独或结合起来预测未来生活的弹性分析-- 和/或健康跨度。我们建议有目的地评估我们的主要假设，重点是弹性。 通过执行以下特定目标(SA)来分析翻译潜力。SA 1将优化弹性 化验方案，每个方案包括一个急性身体挑战和相关的最佳恢复指标 年龄和挑战使用的严重程度。SA 2将确定弹性分析是否在特定情况下进行了优化 目标1可以确定已知的延长寿命或健康的治疗方法的影响。三种这样的治疗将是 与未经治疗的对照组相比。它们是：(A)饮食限制(DR)。这可以被认为是一个积极的 控制力。为了提供信息，我们的弹性分析应该预测两性更长的寿命；(B)雷帕霉素，我们的 弹性分析应该可以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更长的寿命。SA 3将评估大多数 成功的恢复力分析在特定的目标2中确定了小鼠的不同基因。因为人类是如此的 由于遗传和环境的多样性，应该最大限度地扩大小鼠检测的普遍性 有可能。不同的小鼠基因类型可用于评估在Aim 2中开发的检测方法是否 与原始测试基因特有，或者像我们希望用于人体试验的那样健壮。

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.