Anti-Geronic Factors, GDF11 and Oxytocin, and Aging-Related Phenotypes

 描述（由申请人提供）：在幼龄小鼠和老龄小鼠之间使用异时异生物共生的开创性实验报告了老龄小鼠中许多年龄相关表型的逆转。这些研究已经确定了生长分化因子11（GDF 11）和催产素作为重要的抗衰老因子。然而，这些抗衰老因子循环水平的年龄相关变化及其与年龄相关的 部分由于测定特异性的问题，对人类群体中的表型仍然知之甚少。我们将表征GDF 11和催产素水平的年龄相关变化，确定它们与年龄相关的临床事件、状况和与贲门、脑、代谢和肌肉骨骼衰老相关的亚临床标志物的关系，并阐明它们在Frachial Heart研究（FHS）后代和Omni队列中的广泛年龄范围的成人中的表观基因组和转录组决定因素，n=3195），并在社区动脉粥样硬化风险（ARIC）研究（n=1966）中重复这些发现。我们将在CALERIE随机试验中确定热量限制对GDF 11和催产素水平的影响。我们的研究的一个主要创新是一个特定的液相色谱串联质谱法测定GDF 11和特异性提取免疫测定催产素，这将克服现存的检测方法的非特异性的问题的发展。目标1将描述FHS后代和Omni队列中男性和女性的循环GDF 11和催产素水平的年龄相关变化，并将这些变化与年龄、性别和种族/民族相关。目的2将在横断面和纵向分析中将GDF 11和催产素水平与年龄相关的临床事件、状况和表型联系起来（主要用于GDF 11：死亡率、CVD事件、痴呆;次要用于心肌质量和功能、认知功能、脑结构、肌肉力量和身体功能;主要用于催产素：死亡率、活动受限、糖尿病、骨折;次要用于握力、步态速度;大脑结构;认知）。我们将评估GDF 11和催产素水平的遗传性，并确定GDF 11和催产素水平变化的DNA甲基化（CpG位点）和转录组（mRNA）相关性，以及它们如何影响GDF 11和催产素水平与年龄相关表型和条件的关系。目的1和2将在ARIC队列中重复。目的3将确定热量限制对GDF 11和催产素水平的影响。探索性中介分析将评估GDF 11与CVD事件的关系（例如，心力衰竭）是否通过其对心肌质量的影响介导，以及其与痴呆症的关系是否通过特定脑区域的结构变化介导。现有FHS和ARIC数据的深度和广度提供了一个独特的机会，通过亚临床衰老相关措施确定GDF 11和催产素的年龄相关变化是否与具有公共卫生重要性的重大衰老相关临床事件有关。我们的项目将促进抗衰老疗法的发展，其目的是修改两个有很大希望的抗衰老因子。

 DESCRIPTION (provided by applicant): Pioneering experiments using heterochronic parabiotic anastomoses between young and older mice have reported the reversal of a number of age-related phenotypes in older mice. These studies have identified the growth differentiation factor 11 (GDF11) and oxytocin as important anti-geronic factors. However, the age- related changes in the circulating levels of these anti-geronic factors and their relation with age-related phenotypes within human populations remain poorly understood, due, in part, to issues of assay specificity. We will characterize age-related changes in GDF11 and oxytocin levels, determine their relation to age-related clinical events, conditions and subclinical markers related to cardia, brain, metabolic, and musculoskeletal aging, and elucidate their epigenomic and transcriptomic determinants in adults over a wide age range in the Framingham Heart Study (FHS) Offspring and Omni cohorts, n=3195), and replicate these findings in Atherosclerosis Risk in Communities (ARIC) Study (n=1966). We will determine the effects of caloric restriction on GDF11 and oxytocin levels in the CALERIE randomized trial. A major innovation of our study is the development of a specific liquid chromatography tandem mass spectrometry assay for GDF11 and a specific extraction immunoassay for oxytocin, which will overcome the problem of nonspecificity of extant assays. Aim 1 will characterize age-related changes in circulating GDF11 and oxytocin levels in men and women in the FHS Offspring and Omni cohorts and relate these changes to age, sex, and race/ethnicity. Aim 2 will relate GDF11 and oxytocin levels in cross-sectional and longitudinal analyses with age-related clinical events, conditions and phenotypes (primary for GDF11: mortality, CVD events, dementia; secondary: myocardial mass and function, cognitive function, brain structure, muscle strength and physical function; primary for oxytocin: mortality, mobility limitation, diabetes, fractures; secondary: grip strength gait speed; brain structure; cognition). We will assess the heritability of GDF11 and oxytocin levels, and identify DNA methylation (CpG sites) and transcriptomic (mRNA) correlates of variation in GDF11 and oxytocin levels and how they impact the relation of GDF11 and oxytocin levels with age-related phenotypes and conditions. Aims 1 and 2 will be replicated in the ARIC cohort. Aim 3 will determine the effects of caloric restriction on GDF11 and oxytocin levels. Exploratory mediator analyses will evaluate whether the relation of GDF11 with CVD events (e.g., heart failure) is mediated through its effects on myocardial mass, and whether its relation to dementia is mediated through structural changes in specific brain regions. The depth and breadth of the existing FHS and ARIC data provides a unique opportunity to determine whether age-related changes in GDF11 and oxytocin are linked to major aging-related clinical events of public health importance through subclinical aging-related measures. Our project will facilitate the development of anti- aging therapies that are aimed at modifying two anti-geronic factors of great promise.