Comprehensive Evaluation of Aging-Related Clinical Outcomes and Geroproteins

 描述(由申请人提供)：我们建议测试小鼠实验，表明循环蛋白可以恢复大脑、心脏和骨骼肌衰老或加速衰老，是否转化为与老年人重要临床结果的相应关联。通过对GDF11的检测，我们在初步研究中证明，这些老年蛋白与冠心病患者的心力衰竭(HF)和动脉粥样硬化性心血管疾病(ASCVD)有关。相反，GDF11和GDF8的拮抗剂类卵泡抑素3则表现出相反的联系。这些发现突显了确定更具体化验的必要性，它们还呼吁对相关的 一般基于人群的队列中的路径。因此，我们将对最先进的LC质谱学、基于适体的蛋白质组学和免疫分析进行系统的比较，以选择适合每种蛋白质的最佳分析方法。然后，我们将利用心血管健康研究和健康老龄化以及身体成分研究这两个大型双民族队列的全面临床表型和非凡的统计能力来有效地检验以下假设。首先，CCL11和β2微球蛋白水平较高，它们会减少小鼠的神经发生，与认知功能受损和痴呆症风险增加有关。其次，在小鼠中，较高的GDF11水平与较低的左心室(LV)质量和心力衰竭风险相关，特别是与保留射血分数(HFpEF)、ASCVD和痴呆症风险相关。第三，较高水平的GDF11和催产素与改善骨骼肌力量和降低行动不便的风险有关。除了这些终点之外，我们还将检查各种不利后果。此外，我们将使用巴尔的摩老龄化纵向研究的数据和样本，描述这些蛋白质的水平在20岁到96岁的寿命中是如何变化的。这些数据将使我们能够分析这些蛋白质的水平如何影响一生中的认知、左室重量和肌肉力量。这项拟议的研究将由一个由PI和调查人员组成的协调小组领导，他们是实验室科学、老年病学、心脏病学、神经病学、肌肉和流动性以及生物统计学领域的领导者。由异种生物和这些蛋白质的基础生物学领域的领导者组成的一个特殊的科学顾问委员会已经并将继续为我们选择多肽和表型提供信息，并指导我们的数据分析。因此，拟议的研究将对人类队列中的这些兴奋蛋白进行全面分析，目的是确定导致残疾和死亡的主要原因的新的治疗靶点。 目前几乎没有有效的治疗方法。

 DESCRIPTION (provided by applicant): We propose to test whether mouse experiments showing that circulating proteins can rejuvenate or accelerate aging in the brain, heart, and skeletal muscle translate into corresponding associations with important clinical outcomes in older adults. Using an assay for GDF11 that has since been determined also to measure its close structural homologue, GDF8, we demonstrated in preliminary studies that these geronic proteins are associated with incident heart failure (HF) and atherosclerotic cardiovascular disease (ASCVD) in cohorts with prevalent coronary disease. By contrast, follistatin-like 3, an antagonist of GDF11 and GDF8, exhibited the opposite associations. These findings highlight the need to identify more specific assays, and they also call for broader investigation of relevant pathways in general population-based cohorts. We will therefore undertake systematic comparisons of state-of-the-art LC mass spectroscopy, aptamer-based proteomics, and immunoassays to select the best assay for each protein. We will then harness the comprehensive clinical phenotyping and exceptional statistical power of two large, biracial cohorts, the Cardiovascular Health Study and the Health Aging, and Body Composition Study to efficiently test the following hypotheses. First, that higher levels of CCL11 and of ß2 microglobulin, which decrease neurogenesis in mice, are associated with impaired cognitive function and increased risk of dementia. Second, that as in mice, higher levels of GDF11 are associated with lower left ventricular (LV) mass and reduced risk of heart failure, particularly with preserved ejection fraction (HFpEF), ASCVD, and risk of dementia. Third, that higher levels of GDF11 and oxytocin are associated with improved skeletal muscle strength and reduced risk of mobility disability. Beyond these endpoints, we will also examine various adverse outcomes. Moreover, we will describe how levels of these proteins vary across the lifespan, from age 20 to 96, using data and specimens from the Baltimore Longitudinal Study of Aging. These data will enable us to analyze how levels of these proteins influence cognition, LV mass, and muscle strength across the life span. The proposed study will be led by a coordinated team of PIs and investigators who are leaders in their fields of laboratory science, geriatrics, cardiology, neurology, muscle and mobility, and biostatistics. An exceptional Scientific Advisory board of leaders in parabiosis and the basic biology of these proteins has and will continue to inform our choices of peptides and phenotypes, and guide analyses of our data. Hence, the proposed study will provide a comprehensive analysis of these exciting proteins in human cohorts with the aim of identifying novel therapeutic targets for major causes of disability and mortality for which few effective treatments are currently available.