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

 描述(由申请人提供)：在年轻和老年小鼠之间使用异慢性异种异体吻合的开创性实验报告了老年小鼠的一些与年龄相关的表型逆转。这些研究已确定生长分化因子11(GDF11)和催产素是重要的抗老年因子。然而，这些抗老年因子循环水平的年龄相关性变化及其与年龄相关的关系 人类群体中的表型仍然知之甚少，部分原因是检测的特异性问题。我们将描述GDF11和催产素水平与年龄相关的变化，确定它们与与年龄相关的临床事件、条件和与心脏、脑、代谢和肌肉骨骼老化相关的亚临床标志物的关系，并在Framingham心脏研究(FHS)后代和OMNI队列(n=3195)中阐明它们在广泛年龄范围的成年人中的表观基因组和转录决定因素，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GDF11和催产素水平的影响。本研究的一个主要创新是建立了GDF11的特异液相色谱质谱分析方法和催产素的特异萃取免疫分析方法，克服了现有分析方法的非特异性问题。目标1将描述FHS后代和OMNI队列中男性和女性循环GDF11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/民族联系起来。目的2将横断面和纵向分析中的GDF11和催产素水平与年龄相关的临床事件、条件和表型(主要是GDF11：死亡率、心血管事件、痴呆；次要因素：心肌质量和功能、认知功能、脑结构、肌肉力量和身体功能；主要因素是催产素：死亡率、活动受限、糖尿病、骨折；次要因素：握力、步速；脑结构；认知)联系起来。我们将评估GDF11和催产素水平的遗传力，并确定GDF11和催产素水平变异的DNA甲基化(CpG位点)和转录(MRNA)相关性，以及它们如何影响GDF11和催产素水平与年龄相关表型和条件的关系。目标1和目标2将在ARIC队列中复制。目的3确定热量限制对GDF11和催产素水平的影响。探索性中介分析将评估GDF11与心血管事件(如心力衰竭)的关系是否通过其对心肌质量的影响来调节，以及其与痴呆的关系是否通过特定脑区的结构变化来调节。现有FHS和ARIC数据的深度和广度为确定GDF11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通过亚临床衰老相关措施联系在一起提供了独特的机会。我们的项目将促进抗衰老疗法的开发，旨在修改两种前景广阔的抗老年因素。

 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.