Senescence and Growth Differentiation Factors as Modifiers of Aging

衰老和生长分化因子作为衰老调节剂

基本信息

批准号：
9894701
负责人：
Nathan K LeBrasseur
金额：
$ 61.66万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894701
关键词：
Address Affect Aging Amino Acid Sequence Antibodies Arteries Basic Science Biological Biological Aging Biological Assay Biological Markers Blood Pressure Blood specimen Body Composition CCL11 gene Cardiopulmonary Cardiovascular system Cell Adhesion Molecules Cell Aging Cells Chronic Chronic Disease Clinical Code Cognitive Cohort Studies Collaborations Data Differentiation and Growth Disease Drug Targeting Elderly Eotaxin Event Excision Forced expiratory volume function GDF11 gene GDF8 gene Gait speed Geroscience Health Health Status Health education Heart failure Human ICD-9 Impairment Incidence Inflammation Innovative Therapy Intervention Liquid Chromatography Longevity Low Prevalence Measures Mediating Mediator of activation protein Memory Methods Mus Muscle Myocardial Infarction Outcome Participant Partner in relationship Phenotype Physical Function Physical Performance Physical activity Plasma Plasminogen Activator Inhibitor 2 Pre-Clinical Model Prevalence Proteins Rejuvenation Research Risk Factors Sampling Sensitivity and Specificity Stroke Structure Testing Therapeutic Intervention Time Study Tissues Translations Vascular remodeling Walking Work activin A adjudicate age related analytical method base cognitive function disability evidence base exercise intervention fall injury falls healthspan innovation lifestyle intervention multidisciplinary multiple chronic conditions neurogenesis novel older men older women prevent processing speed programs randomized trial regenerative senescence tandem mass spectrometry tissue regeneration

项目摘要

PROJECT SUMMARY/ABSTRACT Aging is the primary risk factor for the majority of chronic diseases. Studies in mice have implicated specific growth and differentiation factors (GDFs) and proteins secreted by senescent cells as potential modifiers of aging. The objective of this proposal is to establish the rationale and provide robust clinical evidence for GDF8, GDF11, and senescence-related proteins eotaxin (CCL11), intracellular adhesion molecule 1 (ICAM1), activin A (AA), and plasminogen activator inhibitor 2 (PAI2), as indicators of biological age and age-related conditions in humans. The central hypothesis is that circulating concentrations of GDFs and senescence-related proteins are associated with, and predictive of, clinically important health outcomes and can be altered by physical activity. Samples from the Lifestyle Interventions and Independence for Elders (LIFE) Study; the largest and longest randomized trial of a physical activity intervention in older adults, will be used to test this hypothesis, and samples from the Health, Aging, and Body Composition (HABC) Study will be used to validate study findings. A novel multiplexed liquid chromatography-tandem mass spectrometry assay will be leveraged to accurately quantify GDFs, and an advanced multiplexing platform will be used to measure senescence-related proteins in LIFE and HABC biospecimens. In Specific Aim 1, a multidisciplinary team will first determine the extent to which baseline concentrations of GDF8, GDF11, CCL11, ICAM1, AA and PAI2 are associated with baseline measures of physical (i.e., gait speed, Short Physical Performance Battery (SPPB) score), cardiopulmonary (i.e., blood pressure, forced expiratory volume), and cognitive (i.e., processing speed, memory) function, inflammation, and prevalence of multimorbidity (based on the ICD-9 codes for 20 chronic conditions). In Specific Aim 2, the degree to which baseline concentrations of GDFs and senescence-related proteins predict longitudinal changes in a) gait speed and SPPB score, b) major mobility disability (i.e., the inability to walk 400m), c) combined cardiovascular events (e.g., myocardial infarction, heart failure, stroke); d) adjudicated falls and injurious falls, e) cognitive function (as Aim 1), and f) the number of chronic conditions (as in Aim 1), at 1 and 2 years in LIFE and at 2 and 4 years in HABC will be determined. Finally, Specific Aim 3 will address whether a structured physical activity intervention impacts longitudinal changes in GDF8, GDF11, CCL11, ICAM1, AA, and PAI2, compared to a health education control intervention, and the degree to which change in the concentrations of these proteins parallel change in the health outcomes described in Aim 2. The successful completion of the proposed research will fill an important translational gap in our understanding of how GDFs and senescence-related proteins predict and, therefore, potentially mediate aging related disability and disease in older women and men. Ultimately, these proteins may be viable targets for innovative therapies to extend human healthspan.

项目概要/摘要衰老是大多数慢性病的主要危险因素。对小鼠的研究表明，特定的生长和分化因子 (GDF) 以及衰老细胞分泌的蛋白质作为潜在的修饰剂老化。该提案的目的是为 GDF8 建立基本原理并提供强有力的临床证据， GDF11、衰老相关蛋白嗜酸细胞趋化因子 (CCL11)、细胞内粘附分子 1 (ICAM1)、激活素 A (AA) 和纤溶酶原激活剂抑制剂 2 (PAI2)，作为生物年龄和年龄相关状况的指标在人类中。核心假设是 GDF 和衰老相关蛋白的循环浓度与临床上重要的健康结果相关并可预测，并且可以通过身体改变活动。老年人生活方式干预和独立（LIFE）研究的样本；最大和对老年人进行体力活动干预的最长随机试验将用于检验这一假设，来自健康、衰老和身体成分 (HABC) 研究的样本将用于验证研究发现。将利用一种新型多重液相色谱-串联质谱分析来准确量化 GDF，并将使用先进的多重平台来测量衰老相关的 LIFE 和 HABC 生物样本中的蛋白质。在具体目标 1 中，多学科团队将首先确定 GDF8、GDF11、CCL11、ICAM1、AA 和 PAI2 的基线浓度与身体基线测量（即步态速度、短期身体表现电池 (SPPB) 分数），心肺（即血压、用力呼气量）和认知（即处理速度、记忆）功能、炎症和多种疾病的患病率（基于 20 种慢性病的 ICD-9 代码）状况）。在具体目标 2 中，GDF 的基线浓度和衰老相关的程度蛋白质预测以下方面的纵向变化：a) 步态速度和 SPPB 评分，b) 主要活动障碍（即无法行走 400m)，c) 合并心血管事件（例如心肌梗塞、心力衰竭、中风）； d) 判定的跌倒和伤害性跌倒，e) 认知功能（如目标 1），以及 f) 慢性疾病的数量（如在目标 1) 中，将在 LIFE 第 1 年和第 2 年以及 HABC 第 2 年和第 4 年确定。最后，具体目标 3 将解决结构化身体活动干预是否影响 GDF8、GDF11 的纵向变化， CCL11、ICAM1、AA 和 PAI2 与健康教育控制干预措施相比，以及影响程度这些蛋白质浓度的变化与目标 2 中描述的健康结果的变化平行。成功完成拟议的研究将填补我们理解中的一个重要转化空白 GDF 和衰老相关蛋白如何预测并因此潜在地介导衰老相关的残疾以及老年女性和男性的疾病。最终，这些蛋白质可能成为创新疗法的可行靶点以延长人类的健康寿命。