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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.

摘要身体弹性是健康老龄化的预测因子（竞争性更新）对身体压力事件做出反应并从中恢复的能力被定义为身体弹性。的对身体压力源的内在个体差异表明，不同的压力源触发不同的压力反应模式更深入地了解为什么有些人保持或恢复功能在侮辱之后，而其他人没有，可能有助于描述可以参与的保护因素，促进恢复力和健康老龄化。我们已经开发并部分表征了三种预防性小鼠的相关身体应激源：急性睡眠中断（ASD），化疗药物环磷酰胺（CTX）和急性皮肤创伤（ACT），引发反应显示相关性具有与年龄增长相关的生理和病理特征。我们在第一批补助金中在此期间，ASD、ASD和ACT给予中年小鼠，从低到高，使得小鼠可以被分类为抗性或易感，并与表型和衰老的老年病理学参数竞争性更新的假设是，其特点是在一个年龄段内，对特定的身体压力源有独特的异质反应模式- 依赖的方式。目的1旨在验证ASD、ASD和ACT的生理目标。反应性将通过读出测定（ASD的学习任务中的逃避时间、中性粒细胞对淋巴细胞比率（以ACT表示）和活检愈合面积（以ACT表示）作为对每一个物理压力。然后将对每组小鼠进行随访至老年，并与表型老化终点包括记忆力、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、ASD和ACT的差异的终点，两组特定器官的老年病理学损伤评分。数字成像和生物统计学小鼠PathoClock分析的范例将用于评价器官特异性和器官共同性老年病理学数据。目的3旨在鉴定和表征ASD、ASD和ACT的分子途径在来自Aim 1小鼠的组织中，并采用RNA seq进行转录组学途径分析，随后进行验证利用纳米级蛋白质分析平台和免疫组织化学成像，应激抵抗和应激易感小鼠中的相关通路。然后，可以将数据与来自目标1和2。对特定组织和器官中细胞利用的分子途径的研究，对身体压力源的反应在预测对衰老的适应力较低的个体中是有价值的，对设计临床研究以促进健康老龄化具有重要意义。