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: 9913819
• 负责人: DEREK Major HUFFMAN
• 金额: $ 7.27万
• 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 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913819
• 关键词: Address; Age; Aging; Biological Assay; Biology of Aging; Body Weight; Cardiovascular system; Cognitive; Detection; Development; Diagnosis; Elderly; Estradiol; Evaluation; Exposure to; Female; Future; Goals; Homeostasis; Homologous Gene; Housing; Human; Infection; Intervention; Longevity; Metabolic; Modeling; Monoclonal Antibodies; Mus; Operative Surgical Procedures; Organism; Outcome; Pharmacology; Physiological; Radiation; Research; Rodent; Sex Differences; Starvation; Stress; Temperature; Testing; Translating; Treatment Efficacy; Validation; Variant; healthspan; healthy aging; male; middle age; neuromuscular; outcome prediction; 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 contribute 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，人们越来越认识到，将啮齿动物安置在传统的、无缘无故的条件下， 与自由生活的人类通常遇到的相同种类的压力源相比，它限制了 我们对如何将这些策略最有效地转化为人类的理解如此定义。 RFA 弹性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，开发了一种简单的短期测定方法来表征啮齿类动物的恢复能力。 可以通过快速、廉价和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。 卓越的恢复能力是健康老龄化和长寿的必要条件，并且优化检测以检测变异 在目标 1 中，我们将建立并优化电池。 功能测试来区分 CB6F1 雄性和雌性小鼠的生理弹性随衰老的变化。 这一目标的目标是通过良好的方法来校准对压力源的响应的应用和检测。 已建立的人类同源物（辐射、饥饿、手术和感染）和直接的反应 我们将考虑在 4、12 和 20 月龄的小鼠中进行测定（即体重、体温等）。 观察到年龄对压力源的敏感性以及增加组内反应的变异性是成功的 随着年龄的增长，这将证实区分良好、平均和较差反应者的潜力 目标 2 中结果的预测因子。在目标 2 中，我们将确定 12 个月大时的复原能力来预测 跨多个领域（认知、心血管、神经肌肉、代谢）以及 在目标 3 中，我们将确定药物干预是否具有性二态性。 对衰老结果的影响相似的性别赋予生理弹性的差异。 通过关注两个方面来验证针对调节寿命的干预措施的弹性优化测试的能力 为此，16 个月大的男性和女性的药理学策略对生存的影响具有显着的性别差异。 使用 17α-雌二醇（优先考虑雄性）和 IGF-1R 单克隆抗体（优先考虑雌性）对小鼠进行 4 个月， 并确定是否可以使用我们优化的电池来检测特定性别的弹性改善 开发、完善和验证易于执行的弹性分析不仅会有所帮助。 弥补衰老研究中的一个重要差距，但将对临床前衰老研究的方式产生重大影响 未来进行。