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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10166754
• 关键词: Acute; Age; Aging; Animal Model; Animals; Biological Assay; Biology of Aging; Biomedical Research; Cause of Death; Clinical Trials; Development; Elderly; Estradiol; Exhibits; Female; Future; Genetic; Genotype; Goals; Health; Healthcare Systems; Homeostasis; Human; Intervention; Life; Life Expectancy; Longevity; Mus; Organism; Pharmacology; Population; Property; Protocols documentation; Recovery; Research; Resistance; Severities; Sex Differences; Sirolimus; Speed; Standardization; Stress; Sum; System; Testing; Time; analog; design; dietary; dietary restriction; disability; global health; healthspan; improved; male; middle age; novel; pre-clinical; predictive test; resilience; senescence; sex; therapy development; trend; virtual; Acute; Age; Aging; Animal Model; Animals; Biological Assay; Biology of Aging; Biomedical Research; Cause of Death; Clinical Trials; Development; Elderly; Estradiol; Exhibits; Female; Future; Genetic; Genotype; Goals; Health; Healthcare Systems; Homeostasis; Human; Intervention; Life; Life Expectancy; Longevity; Mus; Organism; Pharmacology; Population; Property; Protocols documentation; Recovery; Research; Resistance; Severities; Sex Differences; Sirolimus; Speed; Standardization; Stress; Sum; System; Testing; Time; analog; design; dietary; dietary restriction; disability; global health; healthspan; improved; male; middle age; novel; pre-clinical; predictive test; resilience; senescence; sex; therapy development; trend; virtual

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.

项目摘要 随着生活，人口的老龄化已成为全球人类健康的第一威胁 预期正在迅速上升，因为衰老几乎是所有主要的死亡，残疾和 后来生活质量的退化。对这种趋势改善的希望在于 增强和扩大健康的治疗方法。评估有希望的化合物的主要限制 感应抑制特性是在小鼠中进行寿命研究所需的时间，这是主要临床前的 生物医学研究采用的动物模型。同样，一旦化合物准备进行人体测试， 完成临床试验所需的时间也将成为瓶颈。为了加快现场进步 然后，开发一个可以在小鼠中进行的短期评估小组的小组是无价的 早在中期，可以预测干预措施是否会扩大小鼠的健康状况。能力 从急性身体挑战或压力中恢复的有机体众所周知，随着年龄的增长而下降。如果我们 将弹性定义为一种定量度量标准，该指标衡量有机体返回的能力和速度 体内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。拟议研究的目的是制定标准化挑战或挑战小组 以及他们的参与恢复指标，这些指标将对假定的HealthSpan影响有所帮助 在早期生活中进行治疗时，健康的干预措施。总体假设 拟议的研究是，可以单独或结合使用的弹性分析预测未来的生活 - 和/或健康跨度。我们建议评估我们的总体假设有目的地关注弹性 通过执行以下特定目的（SAS），具有翻译潜力的测定。 SA 1将优化弹性 测定协议，每种方案包括急性物理挑战和相关的恢复指标 使用挑战的年龄和严重性。 SA 2将确定是否在特定的 AIM 1可以识别已知的寿命或健康跨度扩展治疗的影响。三种这样的治疗将是 与未处理的对照相比。这些是：（a）饮食限制（DR）。这可以被认为是积极的 控制。为了提供信息，我们的弹性测定法应该预测两性寿命。 （b）雷帕霉素，我们的 弹性测定应预测两性寿命的较长寿命，但在女性中的影响更大。 （c）17-α-雌二醇。 我们的弹性法案只能预测男性的更长寿命。 SA 3将评估最大的鲁棒性 在小鼠基因型的特定目标2中鉴定出的成功弹性测定。因为人类是如此 在属上和环境上，小鼠测定的一般性应最大化 可能的。无论AIM 2中开发的测定是否为 正如我们想要的人类试验那样，对原始测试基因型或可靠的特质。