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

 描述(申请人提供)：老龄化是大多数慢性病的主要危险因素。在小鼠身上的研究表明，衰老细胞分泌的特定生长和分化因子(GDF)和蛋白质可能是衰老的修饰物。作为对RFA AG16102的回应，这项建议的目的是建立GDF8、GDF11和衰老相关蛋白嗜酸性粒细胞趋化蛋白(CCL11)、细胞内黏附分子1(ICAM1)和纤溶酶原激活物抑制物2(PAI2)作为衰老相关疾病的新治疗靶点的理论基础和强有力的临床证据。中心假设是，循环中的GDF和衰老相关蛋白的浓度与临床上重要的健康结果相关，并可以预测，并且可以通过体力活动来改变。生活方式干预和老年人独立性(LIFE)研究的样本将用于验证这一假设。LIFE是对老年人进行体力活动干预的规模最大、持续时间最长的随机试验。将利用一种新的多路复用液相色谱-串联质谱仪分析来准确地定量GDF，并将使用一个先进的多路复用平台来测量生命研究参与者血浆中与衰老相关的蛋白质。在具体目标1中，一个多学科小组将首先确定GDF8、GDF11、CCL11、ICAM1和PAI2的基线浓度与身体(即步速和短身体表现电池(SPPB)评分)、心肺(即血压、用力呼气量和最大吸气压力)、认知(即处理速度和记忆)功能和多发性疾病(基于19种慢性病的ICD-9代码)的基线测量之间的关联程度。在具体目标2中，将确定在12个月和24个月的研究时间点，GDF和衰老相关蛋白的基线浓度在多大程度上预测a)步速和SPPB评分，b)主要活动障碍(即，无法行走400米)，c)合并心血管事件(例如，心肌梗死，中风，外周动脉疾病)，d)被判定的跌倒和损伤性跌倒，e)认知功能(作为目标1)，以及f)慢性疾病的数量(如目标1)。最后，特定的目标3将解决与健康教育控制干预相比，结构化体力活动干预是否影响GDF8、GDF11、CCL11、ICAM1和PAI2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潜在地调节老年女性和男性衰老相关残疾和疾病的理解的一个重要的翻译空白。最终，这些蛋白质可能成为延长人类健康寿命的创新疗法的可行靶点。

 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.