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

评估弹性作为小鼠健康寿命预测因子的性别差异方法

基本信息

批准号：
10166754
负责人：
STEVEN N. AUSTAD
金额：
$ 30.44万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2023-05-31
项目状态：
已结题

项目摘要

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.

项目概要人口老龄化已成为全球人类健康的第一大威胁预期值正在迅速上升，因为老龄化几乎是导致死亡、残疾和死亡的所有主要原因。晚年生活质量下降。改善这一趋势的希望在于增强和延长健康的治疗。评估有前途的化合物的主要限制衰老抑制特性是在小鼠中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。为了加快该领域的进展那么，开发一组可以对小鼠进行短期检测的方法将是非常有价值的。早年到中年的研究可以预测干预措施是否会延长小鼠的健康寿命。的能力众所周知，从严重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定量指标，衡量有机体恢复状态的能力和速度身体压力或挑战后的体内平衡，然后延长生命和健康的干预措施通常会增强弹力。拟议研究的目标是制定标准化挑战或挑战小组及其随附的恢复指标，这些指标将为有关假定的健康寿命影响提供信息在生命早期到中期实施的健康扩展干预措施。的总体假设拟议的研究是，可以开发弹性测定法来单独或组合地预测未来的生活- 和/或健康跨度。我们建议评估我们的总体假设，重点关注弹性通过执行以下特定目标 (SA) 进行具有转化潜力的测定。 SA 1 将优化弹性检测方案，每个方案都包含急性身体挑战和相关的最佳恢复指标年龄和使用挑战的严重程度。 SA 2 将确定弹性测定是否在特定方面进行了优化目标 1 可以确定已知的寿命或健康寿命延长治疗的影响。三种这样的治疗方法将与未处理的对照相比。它们是： (a) 饮食限制 (DR)。这可以被认为是积极的控制。为了提供信息，我们的复原力测定应该预测两性的寿命更长。 (b) 雷帕霉素，我们的复原力测定应该可以预测两性的寿命都会更长，但对女性的影响更大； (c) 17-α-雌二醇。我们的复原力测定应该只能预测男性的寿命更长。 SA 3 将评估最在特定目标 2 中成功地确定了跨小鼠基因型的弹性测定。因为人类是如此由于遗传和环境的多样性，小鼠检测的通用性应最大化可能的。可以使用不同的小鼠基因型来了解目标 2 中开发的测定是否有效与原始测试基因型不同，或者像我们希望的人体试验那样稳健。