Aging and Resiliency in Mice: Optimizing Assessment Protocols and Testing Interventions

小鼠的衰老和恢复能力：优化评估方案和测试干预措施

基本信息

批准号：
9918217
负责人：
Nathan K LeBrasseur
金额：
$ 39.64万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918217
关键词：
Acute Affect Age Age-Months Aging Anesthesia procedures Animal Model Attenuated Biological Biological Aging Biological Markers Biology of Aging Body Weight CDKN2A gene Cardiovascular Physiology Cardiovascular system Cell Aging Cells Chronic Disease Clinic Cytotoxic agent Dehydration Disease Elderly Evaluation Excision Exhibits FRAP1 gene Future Genetic Glucose Health Human Immune Innovative Therapy Intervention Laboratory mice Left Ventricular Mass Life Longevity Maintenance Measures Mediating Mediator of activation protein Metabolic Michigan Molecular Mus Operative Surgical Procedures Organism Osmolalities Outcome Physical assessment Physiological Plasma Protocols documentation Public Health Recovery Resources Signal Transduction Sirolimus Standardization Stress Surrogate Markers Syndrome System T-Lymphocyte Subsets Testing Therapeutic Therapeutic Intervention Time Transgenes Universities Work age group aging population blood glucose regulation cell injury cellular targeting chemotherapy clinically relevant cohort disability exercise capacity experience frailty healthspan healthy aging immune function indexing innovation middle age mortality peer resilience response senescence

项目摘要

PROJECT SUMMARY/ABSTRACT Therapeutic interventions that target fundamental mechanisms of aging are being sought to radically transform public health. Indicators of biological aging that can be identified prior to overt manifestations of late-life conditions, and concomitantly serve as predictors of future health and longevity, could facilitate this effort. As highlighted in this RFA, resilience, defined as the ability of an organism to adequately respond to physical challenges, may offer one such opportunity. Thus, the objective of this proposal is to develop and validate a battery of disease-agnostic physical challenges to enable the evaluation of resiliency in mice. To this end, in Specific Aim 1 we will determine which physical challenges best reveal differences in resilience between and within younger, middle-aged, and older mice. Specifically, we will assess acute responses to anesthesia, chemotherapy, surgery, and dehydration in cohorts of 4-month-old, 12-month-old, and 20-month-old mice. In Specific Aim 2, using the physical challenges deemed optimal in Specific Aim 1, we will determine the extent to which baseline resilience of middle-aged mice longitudinally predicts healthspan using discriminating measures of physical, metabolic, cardiovascular, and immune function at Mayo Clinic, and lifespan at the University of Michigan. Given the considerable evidence that aberrant mTOR signaling and senescent cell accumulation are mediators of aging, in Specific Aim 3 we will determine the extent to which rapamycin and targeted clearance of p16INK4a-positive senescent cells affect the resilience of older mice to physical challenges. We expect that a standardized battery of clinically relevant measures of resilience in laboratory mice will provide a new framework in which to test innovative and potentially transformative interventions to promote healthy aging. In humans, the emergence of chronic diseases and syndromes such as frailty may reflect a point of no return. Compromised resilience earlier in life, on the other hand, may ultimately serve as a therapeutic opportunity in which the progression of aging-related molecular and cellular damage can be attenuated, if not reversed.

项目概要/摘要人们正在寻求针对衰老基本机制的治疗干预措施，以从根本上改变公共卫生。在明显的晚年表现之前可以识别的生物衰老指标条件，并同时作为未来健康和寿命的预测因素，可以促进这一努力。作为本次 RFA 强调了复原力，定义为有机体对物理现象做出充分反应的能力。挑战，可能会提供这样的机会。因此，本提案的目标是开发和验证一系列与疾病无关的身体挑战能够评估小鼠的弹性。为此，在具体目标 1 我们将确定哪些身体挑战最能揭示和之间的复原力差异在年轻、中年和老年小鼠中。具体来说，我们将评估对麻醉的急性反应，对 4 个月大、12 个月大和 20 个月大的小鼠组进行化疗、手术和脱水。在具体目标 2，使用具体目标 1 中认为最佳的身体挑战，我们将确定中年小鼠的基线弹性使用区分措施纵向预测健康寿命梅奥诊所的身体、代谢、心血管和免疫功能以及英国大学的寿命密歇根州。鉴于大量证据表明异常的 mTOR 信号传导和衰老细胞积累是衰老介质，在具体目标 3 中，我们将确定雷帕霉素和靶向清除的程度 p16INK4a 阳性衰老细胞的数量会影响老年小鼠应对身体挑战的能力。我们期望一个实验室小鼠临床相关弹性测量的标准化电池组将提供新的方法测试创新和潜在变革性干预措施以促进健康老龄化的框架。在对人类来说，慢性疾病和虚弱等综合症的出现可能反映出一个不归路。另一方面，生命早期的复原力受损最终可能成为治疗的机会与衰老相关的分子和细胞损伤的进展即使不能逆转，也可以减弱。