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.

摘要身体复原力是健康衰老的预测指标（竞争性更新）应对身体压力事件并从中恢复的能力被定义为身体复原力。这对身体压力源的反应存在固有的个体差异，这表明不同的压力源会引发不同的反应压力反应模式。更深入地了解为什么某些人保持或恢复功能受到侮辱后，而其他人则不然，可能有助于描述可以参与的保护因素促进复原力和健康老龄化。我们已经开发并部分表征了三种翻译小鼠相关的身体压力源：急性睡眠中断（ASD）、化疗药物环磷酰胺 (CYP) 和急性皮肤创伤 (ACT)，触发的反应显示出相关性具有与年龄增长相关的生理和病理特征。我们已经在第一笔拨款中展示了在此期间，对中年小鼠施用 ASD、CYP 和 ACT 会导致一系列反应：从低到高，这样小鼠就可以被归类为耐药或易感，并与表型和衰老的老年病理学参数。竞争更新的假设是，对衰老的恢复力其特点是不同年龄阶段所定义的身体压力源所特有的异质反应模式。依赖方式。目标 1 旨在验证 ASD、CYP 和 ACT 的生理目标。反应性将通过读数测定来确定（自闭症谱系障碍（ASD）学习任务中的逃逸时间、中性粒细胞到 CYP 的淋巴细胞比率和 ACT 的活检愈合面积）对中年小鼠的耐药性或易感性每个身体压力源。然后对每组小鼠进行跟踪直至其年龄较大并与表型进行比对衰老终点包括记忆力、力量和敏捷性的评估。目标 2 旨在确认器官使用基于 Aim 1 小鼠组织中 ASD、CYP 和 ACT 的目标，使用基于差异的终点两组特定器官的老年病理学病变评分。数字成像和生物统计小鼠 PathoClock 分析范例将用于评估器官特异性和器官共同性老年病理学数据。目标 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，利用 RNA seq 进行转录组通路分析，然后进行验证具有纳米级蛋白质分析平台和免疫组织化学成像，用于分子分析抗应激和应激易感小鼠的相关途径。然后可以将数据与来自的数据对齐目标 1 和 2. 研究特定组织和器官中细胞利用的分子途径对于预计对衰老的抵抗力较差的个体来说，对身体压力源的反应是有价值的，并且对于设计促进健康老龄化的临床研究具有重要意义。