Senescence and Growth Differentiation Factors as Modifiers of Aging

项目摘要/摘要 老龄化是大多数慢性病的主要危险因素。对小鼠的研究表明， 衰老细胞分泌的生长和分化因子(GDF)和蛋白质作为潜在的修饰因子 衰老。这项建议的目的是建立GDF8的理论基础并提供强有力的临床证据， GDF11、衰老相关蛋白嗜酸粒细胞趋化蛋白(CCL11)、细胞内黏附分子1(ICAM1)、激活素 A(AA)和纤溶酶原激活物抑制物2(PAI2)，作为生物年龄和年龄相关状况的指标 在人类身上。中心假设是循环中GDFS和衰老相关蛋白的浓度 与临床上重要的健康结果相关，并可预测，并且可以通过物理改变 活动。生活方式干预和老年人独立性(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被用来检验这一假设， 来自健康、老龄化和身体成分(HABC)研究的样本将用于验证研究 调查结果。一种新的多重液相色谱-串联质谱分析将被用于 精确量化GDF，并将使用先进的多路复用平台来测量与衰老相关的 生命中的蛋白质和HABC生物有机体。在具体目标1中，一个多学科小组将首先确定 GDF8、GDF11、CCL11、ICAM1、AA和PAI2的基线浓度与 体能的基线测量(即步态速度、短体能电池(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、炎症和多发病(基于20种慢性疾病的ICD-9编码 条件)。在具体目标2中，GDF的基线浓度与衰老相关的程度 蛋白质预测a)步速和SPPB评分的纵向变化，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、心力衰竭、中风)；d) 判定跌倒和伤害性跌倒，e)认知功能(目标1)，以及f)慢性病的数量(AS 在目标1)中，将确定人生1岁和2岁，以及在HABC的2岁和4岁。最后，具体目标3将 解决结构化体力活动干预是否影响GDF8、GDF11、 CCL11、ICAM1、AA和PAI2，与健康教育控制干预进行比较，以及 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是平行的。 拟议研究的成功完成将填补我们在理解 GDF和衰老相关蛋白如何预测并因此潜在地调节衰老相关的残疾 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。

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.