Optimizing resilience assays for biology of aging research in mice

优化小鼠衰老研究生物学的弹性测定

• 批准号: 10166753
• 负责人: DEREK Major HUFFMAN
• 金额: $ 34.24万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10166753
• 关键词: Address; Age; Aging; Biological Assay; Biology of Aging; Body Weight; Cardiovascular system; Cessation of life; Chronic Disease; Cognitive; Coupled; Detection; Development; Diagnosis; Elderly; Ensure; Environment; Estradiol; Evaluation; Exposure to; Female; Future; Goals; Homeostasis; Homologous Gene; Housing; Human; Impairment; Individual; Infection; Intervention; Longevity; Measures; Metabolic; Methods; Modeling; Monoclonal Antibodies; Mus; Operative Surgical Procedures; Organism; Outcome; Pharmacology; Physiological; Protocols documentation; Radiation; Research; Rodent; Sex Differences; Starvation; Stress; System; Temperature; Testing; Translating; Treatment Efficacy; Validation; Variant; chemotherapy; cohort; design; frailty; healthspan; healthy aging; male; middle age; multiple chronic conditions; neuromuscular; outcome prediction; physiologic stressor; pre-clinical; prognostic; resilience; response; sex; sexual dimorphism; stressor

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.

提案摘要 寿命和健康寿命的评估仍然是记录衰老研究功效的基石。 人们越来越认识到，将啮齿动物安置在传统的、无端的条件下，而不是 暴露于自由生活的人类通常会遇到的相同种类的压力源，限制了我们 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。 复原力是指有机体能够应对身体挑战或压力并恢复正常状态的能力。 体内平衡随着年龄的增长而下降，可能导致并可能成为发生的基础。 因此，早年或中年的恢复能力可以预测未来的健康寿命和寿命。 因此，开发一种简单、短期的分析方法来表征啮齿类动物的恢复力可以 通过提供快速、廉价且全面的诊断策略，彻底改变衰老研究 干预效果，对未来结果可能有预测价值，因此，我们提出了一系列的建议。 简单、多样的挑战和检测，包括选择性手术、放射、饥饿和感染模型 表征啮齿动物的恢复能力，以预测未来的结果。 复原力是健康老龄化和长寿所必需的，并且优化检测以检测复原力的变化 可以预测长期衰老结果 在目标 1 中，我们将建立并优化一组功能。 测试区分 CB6F1 雄性和雌性小鼠的生理弹性随衰老的变化。 这一目标是用公认的人类标准来校准压力源反应的应用和检测。 同系物（辐射、饥饿、手术和感染）和直接反应测定（即 体重、体温等）在 4、12 和 20 月龄的小鼠中，我们将认为实施成功。 观察到年龄对压力源的敏感性以及随着年龄的增长而增加的组内反应变异性， 这将确认区分良好、平均和不良反应者作为结果预测因素的潜力 目标 2。在目标 2 中，我们将确定 12 个月大时的恢复能力，以预测未来的健康寿命 在目标 3 中，我们将关注多个领域（认知、心血管、神经肌肉、代谢）以及长寿。 确定药物干预是否对衰老结果具有性别二态性影响 在生理弹性方面具有相似的性别差异。该目标将尝试验证优化的能力。 通过关注两种药理学策略来测试对调节寿命的干预措施的恢复力 为此，16 个月大的雄性和雌性小鼠服用 17α-雌二醇 4 个月， 优先考虑男性，IGF-1R mAb，优先考虑女性，并确定是否具有性别特异性 弹性的改善可以通过我们优化的一系列检测来检测。 易于执行的弹性测定的验证不仅有助于解决衰老方面的重要差距 研究，但将对未来如何进行临床前衰老研究产生重大影响。