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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.

身体弹性是健康衰老（竞争性更新）的预测因子