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。然而，在这方面， 越来越多的人认识到，在传统的、无端的条件下饲养啮齿动物，而不是 暴露在自由生活的人类通常会遇到的各种压力下，限制了我们的 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 弹性是一种生物体能够对身体挑战或压力做出反应并恢复的能力。 体内平衡生理弹性随着年龄的增长而下降，可能导致并可能导致 与老化有关的条件。因此，生命早期或中期的韧性可能预示着未来的健康寿命和寿命。 因此，开发一种简单、短期的测定方法来表征啮齿动物的复原力， 通过快速、廉价和全面的战略来诊断， 干预效果，对未来结果可能具有预测价值。因此，我们提出了一个电池， 简单，多样化的挑战和分析，包括选择性手术，辐射，饥饿和感染模型 描述啮齿动物的复原力，以预测未来的结果。我们假设， 弹性是健康衰老和长寿的必要条件，并且该分析经过优化以检测弹性的变化 可以预测长期老化的结果。在目标1中，我们将建立和优化一组功能 测试以区分CB 6 F1雄性和雌性小鼠中生理弹性随衰老的变化。的目标 这一目的是校准应用和检测的反应，以紧张性刺激与完善的人类 同源物（辐射、饥饿、手术和感染）和直接响应测定（即， 体重、体温等）。我们认为， 观察到年龄对压力源的敏感性，以及随着年龄的增长，反应的组内变异性增加， 这将证实区分良好、一般和不良反应者作为结果预测因子的潜力 目标2在目标2中，我们将确定12个月龄时的恢复能力，以预测未来的健康寿命。 多个领域（认知、心血管、神经肌肉、代谢）以及寿命。在目标3中，我们 确定药物干预是否对衰老结局具有已证实的性二态效应 在生理弹性上也有类似的性别差异。本目标将尝试验证优化的 通过关注两种药理学策略来调节寿命的干预措施的弹性测试， 在生存率上存在显著的性别差异。为此，将16月龄雄性和雌性小鼠用17α-雌二醇， 其偏好男性，IGF-1 R mAb偏好女性，并确定是否性别特异性 可以使用我们优化的一系列测定来检测弹性的改善。发展，完善， 并且验证容易进行的恢复力测定不仅有助于解决老化的重要差距， 研究，但将对未来如何进行临床前衰老研究产生重大影响。