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是否表明循环蛋白质可以恢复或加速大脑，心脏和骨骼肌的衰老，并将其转化为与老年人重要临床结果的相应关联。使用GDF11的测定，该测定也被确定用于测量其密切的结构同源物GDF8，我们在初步研究中证明，这些老年蛋白与流行性冠状动脉疾病队列中的偶发性心力衰竭（HF）和动脉粥样硬化性心血管疾病（ASCVD）相关。相比之下，卵泡抑素样3，GDF11和GDF8的拮抗剂，表现出相反的关联。这些发现强调了需要确定更具体的检测方法，他们还呼吁对相关的 在一般人群为基础的队列的途径。因此，我们将进行最先进的LC质谱，基于适体的蛋白质组学和免疫测定的系统比较，以选择每种蛋白质的最佳测定。然后，我们将利用综合临床表型和两个大型birthday队列，心血管健康研究和健康老龄化和身体成分研究的特殊统计能力，有效地测试以下假设。首先，CCL11和β 2微球蛋白水平升高会降低小鼠的神经发生，与认知功能受损和痴呆风险增加有关。第二，在小鼠中，较高水平的GDF11与较低的左心室（LV）质量和降低的心力衰竭风险相关，特别是与保留射血分数（HFpEF），ASCVD和痴呆风险相关。第三，更高水平的GDF11和催产素与骨骼肌力量的改善和移动残疾风险的降低有关。除了这些终点，我们还将检查各种不良结局。此外，我们将描述这些蛋白质的水平如何在整个生命周期中变化，从20岁到96岁，使用来自巴尔的摩老龄化纵向研究的数据和标本。这些数据将使我们能够分析这些蛋白质的水平如何影响整个生命周期的认知，LV质量和肌肉力量。拟议的研究将由PI和研究人员组成的协调团队领导，他们是实验室科学，老年病学，心脏病学，神经病学，肌肉和移动性以及生物统计学领域的领导者。一个由联体共生和这些蛋白质的基础生物学领导者组成的特殊科学咨询委员会已经并将继续为我们选择肽和表型提供信息，并指导我们的数据分析。因此，拟议的研究将提供对人类队列中这些令人兴奋的蛋白质的全面分析，目的是为残疾和死亡的主要原因确定新的治疗靶点， 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.