Physical resilience is a predictor of healthy aging

身体弹性是健康衰老的预测指标

基本信息

批准号：
10731992
负责人：
Warren C LADIGES
金额：
$ 67.3万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10731992
关键词：
Acute Age Aging Area Biological Assay Biometry Biopsy Body fat Categories Cells Characteristics Classification Clinical Research Cutaneous Cyclophosphamide Data Diabetes Mellitus Disease Ear Elderly Evaluation Funding Goals Grant Health Heart Diseases Immunohistochemistry Impaired cognition Individual Insulin Resistance Intervention Investigation Learning Lesion Life Lymphocyte Malignant Neoplasms Measures Memory Memory Loss Molecular Molecular Analysis Mus Muscle Organ Parents Pathologic Pathway Analysis Pathway interactions Patients Pattern Peripheral Pharmaceutical Preparations Phenotype Physically Challenged Physiological Predisposition Proteins Public Health Punch Biopsy Resistance Rheumatoid Arthritis Risk Factors Sleep disturbances Stress Stressful Event System Therapeutic Thinness Tissues Trauma Wound models age related biological adaptation to stress chemotherapeutic agent design digital imaging gene product healing healthy aging human old age (65+)individual variation luminescence middle age molecular imaging muscle form nanoscale neutrophil pre-clinical promote resilience protective factors resilience response stressor therapeutic target tissue repair trait transcriptome sequencing transcriptomics wound

项目摘要

Abstract Physical resilience is a predictor of healthy aging (Competitive renewal) The ability to respond to and recover from a physically stressful event is defined as physical resilience. The inherent individual variation in response to a physical stressor suggests that different stressors trigger different stress response patterns. A deeper understanding as to why some individuals maintain or regain function following an insult, while others do not, may help to characterize protective factors that can be engaged to promote resilience and healthy aging. We have developed and partially characterized three translationally relevant physical stressors in mice: acute sleep disruption (ASD), the chemotherapeutic drug cyclophosphamide (CYP), and acute cutaneous trauma (ACT), that trigger responses showing a correlation with physiological and pathological features associated with increasing age. We have shown in the first grant period that ASD, CYP, and ACT administered to middle-aged mice results in a range of responsiveness from low to high, such that mice can be categorized as resistant or susceptible and aligned with phenotypic and geropathologic parameters of aging. The hypothesis of the competitive renewal is that resilience to aging is characterized by heterogeneous response patterns unique to defined physical stressors in an age- dependent manner. Aim 1 is designed to validate physiological targets of ASD, CYP, and ACT. Responsiveness will be determined by readout assays (escape times in a learning task for ASD, neutrophil to lymphocyte ratio for CYP, and biopsy healing area for ACT) in middle aged mice as resistant or susceptible to each physical stressor. Each group of mice will then be followed to older age and aligned with phenotypic aging endpoints including assessments for memory, strength and agility. Aim 2 is designed to confirm organ- based targets of ASD, CYP, and ACT in tissues from Aim 1 mice using endpoints based on differences in geropathology lesion scores in specific organs from the two groups. Digital imaging and biostatistical paradigms for mouse PathoClock analyses will be used for evaluation of organ-specific and organ-common geropathology data. Aim 3 is designed to identify and characterize molecular pathways of ASD, CYP, and ACT in tissues from Aim 1 mice and employ RNA seq for transcriptomic pathway analysis followed by verification with nanoscale protein analytical platforms and immunohistochemistry imaging for molecular analysis of relevant pathways in stress resistant and stress susceptible mice. The data can then be aligned with data from Aims 1 and 2. Investigations into the molecular pathways utilized by cells in a particular tissue and organ in response to a physical stressor would be of merit in individuals predicted to be less resilient to aging and would have impactful significance for designing clinical studies to enhance healthy aging.

抽象的物理弹性是健康衰老的预测指标（竞争性更新）从身体压力的事件中响应和恢复的能力定义为身体弹性。这响应物理压力源的固有的个体变异表明，不同的压力源会触发不同压力反应模式。关于某些人为什么维持或恢复功能的更深入的理解侮辱后，而其他人则没有，可能有助于表征可以参与的保护因素促进弹性和健康衰老。我们已经开发并部分地在三个翻译上进行了表征小鼠的相关身体压力源：急性睡眠中断（ASD），化学治疗药物环磷酰胺（CYP）和急性皮肤创伤（ACT），触发反应显示相关性具有与年龄增长有关的生理和病理特征。我们在第一个赠款中显示了 ASD，CYP和ACT给予中年小鼠的时期导致一系列反应性低到高，使小鼠可以归类为抗性或易感性，并与表型和对齐老化的老年病理参数。竞争更新的假设是对衰老的弹性其特征是在年龄中定义的身体压力源独有的异质响应模式 - 依赖方式。 AIM 1旨在验证ASD，CYP和ACT的生理靶标。响应能力将由读取分析（逃生时间在ASD的学习任务中，中性粒细胞到 CYP的淋巴细胞比，在中年小鼠中为ACT的活检愈合区域，以抗性或容易受到影响每个身体压力源。然后，每组小鼠将遵循年龄，并与表型对齐老化终点，包括评估记忆力，力量和敏捷性。 AIM 2旨在确认器官基于基于端点的ASD，CYP和ASD的基于AIM 1小鼠的组织的靶标，两组的特定器官中的细胞病理病变评分。数字成像和生物统计学小鼠病原体分析的范例将用于评估器官特异性和器官通用老年病理数据。 AIM 3旨在识别和表征ASD，CYP和ACT的分子途径在AIM 1小鼠的组织中，使用RNA SEQ进行转录组途径分析，然后进行验证纳米级蛋白分析平台和免疫组织化学成像，用于分子分析耐应力和应激易感小鼠的相关途径。然后可以将数据与来自目标1和2。对特定组织中细胞使用的分子途径的研究对身体压力源的反应在被预测对衰老的弹性较小的个体中有优势对于设计临床研究以增强健康衰老的意义。