Senescence-related Proteins and Growth and Differentiation Factors as Modifiers of Aging

 描述（由申请人提供）：衰老是大多数慢性病的主要风险因素。对小鼠的研究表明，衰老细胞分泌的特异性生长和分化因子（GDF）和蛋白质是衰老的潜在调节剂。作为对RFA AG 16102的回应，本提案的目的是确立GDF 8、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）和纤溶酶原激活物抑制剂2（PAI 2）作为衰老相关疾病的新型治疗靶点的基本原理并提供可靠的临床证据。中心假设是GDF和衰老相关蛋白的循环浓度与临床重要的健康结果相关并可预测临床重要的健康结果，并且可通过体力活动改变。来自生活方式干预和老年人独立性（LIFE）研究的样本;老年人体力活动干预的最大和最长的随机试验，将用于检验这一假设。一种新型的多重液相色谱-串联质谱分析将被用来准确地定量GDF，一种先进的多重平台将被用来测量LIFE研究参与者血浆中的衰老相关蛋白。在具体目标1中，多学科团队将首先确定GDF 8、GDF 11、CCL 11、ICAM 1和PAI 2的基线浓度与基线物理测量（即，步态速度和短体力活动成套测验（SPPB）评分），心肺（即，血压、用力呼气量和最大吸气压），和认知（即，处理速度和记忆）功能，以及多发性硬化症的患病率（基于19种慢性病的ICD-9编码）。在特定目标2中，GDF和衰老相关蛋白的基线浓度预测a）步态速度和SPPB评分，B）主要移动性残疾（即，不能行走400米），c）合并的心血管事件（例如，心肌梗塞、中风、外周动脉疾病）; 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）慢性疾病的数量（如目标1）。最后，具体目标3将讨论与健康教育对照干预相比，结构化体力活动干预是否会影响GDF 8、GDF 11、CCL 11、ICAM 1和PAI 2的纵向变化，以及这些蛋白质浓度的变化在多大程度上平行于目标2中描述的健康结果的变化。拟议研究的成功完成将填补我们对GDF和衰老相关蛋白如何预测并因此可能介导老年女性和男性中与衰老相关的残疾和疾病的理解的重要翻译空白。最终，这些蛋白质可能成为创新疗法的可行靶点，以延长人类健康寿命。

 DESCRIPTION (provided by applicant): 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. In response to RFA AG16102, 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), and plasminogen activator inhibitor 2 (PAI2), as novel therapeutic targets for aging-related conditions. 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. 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 Study participants' plasma. In Specific Aim 1, a multidisciplinary team will first determine the extent to which baseline concentrations of GDF8, GDF11, CCL11, ICAM1, and PAI2 are associated with baseline measures of physical (i.e., gait speed and Short Physical Performance Battery (SPPB) score), cardiopulmonary (i.e., blood pressure, forced expiratory volume, and maximum inspiratory pressure), and cognitive (i.e., processing speed and memory) function, and prevalence of multimorbidity (based on the ICD-9 codes for 19 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, stroke, peripheral artery disease); d) adjudicated falls and injurious falls, e) cognitive function (as Aim 1), and f) the number of chronc conditions (as in Aim 1), at the 12 and 24 month study time points will be determined. Finally, Specific Aim 3 will address whether a structured physical activity intervention impacts longitudinal changes in GDF8, GDF11, CCL11, ICAM1, 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.