Senescence and Growth Differentiation Factors as Modifiers of Aging

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， 生长和分化因子（GDF）和由衰老细胞分泌的蛋白质作为衰老的潜在调节剂， 衰老本提案的目的是确定GDF 8的基本原理并提供可靠的临床证据， GDF 11和衰老相关蛋白嗜酸性粒细胞趋化因子（CCL 11）、细胞内粘附分子1（ICAM 1）、激活素 A（AA）和纤溶酶原激活物抑制剂2（PAI 2）作为生物学年龄和年龄相关疾病的指标 在人类身上。中心假设是，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，并可预测这些结果，并且可以通过身体因素改变 活动来自生活方式干预和老年人独立性（LIFE）研究的样本;最大的， 在老年人中进行的最长的体力活动干预随机试验，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 调查结果。一种新型的多重液相色谱-串联质谱分析将被利用， 精确量化GDF，先进的多路复用平台将用于测量衰老相关的 LIFE和HABC生物标本中的蛋白质。在具体目标1中，一个多学科小组将首先确定 GDF 8、GDF 11、CCL 11、ICAM 1、AA和PAI 2的基线浓度与下列因素相关的程度： 基线物理测量（即，步态速度，短体力活动成套测验（SPPB）评分）， 心肺（即，血压，用力呼气量），和认知（即，处理速度， 记忆）功能、炎症和多病患病率（基于20种慢性病的ICD-9代码 条件）。在具体目标2中，基线GDF浓度和衰老相关性的程度 蛋白质预测a）步态速度和SPPB评分的纵向变化，B）主要的移动性残疾（即，的 不能行走400米），c）合并的心血管事件（例如，心肌梗死、心力衰竭、中风）; d） 判定的福尔斯和损伤性福尔斯，e）认知功能（如目标1），和f）慢性病症的数量（如 在目标1）中，将确定LIFE中1年和2年以及HABC中2年和4年的剂量。第3章具体目标 解决结构化体力活动干预是否影响GDF 8，GDF 11， CCL 11、ICAM 1、AA和PAI 2与健康教育对照干预相比， 这些蛋白质浓度的变化与目标2所述的健康结果的变化平行。的 成功完成拟议的研究将填补我们理解的一个重要的翻译空白， GDF和衰老相关蛋白如何预测并因此可能介导衰老相关残疾 和老年人的疾病。最终，这些蛋白质可能成为创新疗法的可行目标 to extend延长human人的healthspan健康.

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.