Metabolomic profile of chronic distress in relation to diseases of aging across diverse populations

各种形式的慢性痛苦与过早衰老和心血管代谢疾病的发展有关。 疾病（CMD）是老年人死亡的主要原因。慢性抑郁和CMD症状 与阿尔茨海默病和阿尔茨海默病相关性痴呆（AD/ADRD）的风险密切相关。 虽然影响血管健康的代谢变化被认为是推动这种关系的关键途径， 之间的慢性困扰和重大疾病的老化，了解分子机制的基础 这种代谢变化是有限的。高通量技术允许同时测量 血浆中的数百种代谢物（“代谢组学”），并提供了一个人的代谢的全貌 profile.在我们的第一个资金周期，我们开发并验证了液相色谱-串联质谱 基于LC-MS的慢性痛苦（焦虑和抑郁）代谢组学评分，独立 主要是非西班牙裔白色女性的数据集;该评分与较高的CMD事件风险相关。在 这次更新，使用尖端的代谢组学和生物统计学方法，沿着几个额外的队列 我们建议扩展我们的初步研究结果，并针对以下具体目标：（1）加强我们的 通过添加新的、以前未知的代谢物， 与窘迫表型相关，并通过生物化学方法鉴定这些经验证但未知的代谢物， 提供新的机制见解;（2）评估我们的慢性痛苦代谢组学评分（及其组成部分）， 关键人群，包括非洲裔美国人（AA）和西班牙裔男性和女性以及白色男性，并优化 每个人群的得分。我们还将评估评分（和组件）与CMD的关联， 其次是AA男性和女性、白色男性的AD/ADRD风险，初步是西班牙裔男性和女性， 和（3）使用因果方法评估慢性痛苦是否影响与痛苦相关的代谢物评分， 评估抑郁-代谢物评分作为慢性抑郁与CMD关系的潜在中介 其次是AD/ADRD风险。我们将通过利用强大的数据资源， 五项前瞻性研究：杰克逊心脏研究（n= 5，306; 100% AA男性和女性），多种族 动脉粥样硬化研究（n= 6，814; 39%白色、28% AA、22%西班牙裔、12%亚裔美国男性和 女性）、护士健康研究（NHS; n= 121，700，98%为白色女性）、女性健康倡议 （n= 161，808例女性; 18%为非白色），PREDIMED（n= 7，447例;白色男性和女性）。每一组都有 类似地评估慢性痛苦、血液代谢组学特征、相关协变量、CMD和痴呆风险 在长达20年的随访中取得的成果。NHS和梅萨也有遗传学数据， 代谢组学测量。这项工作将扩展我们对慢性炎症的生物学途径的理解。 抑郁及其与随后的CMD和痴呆症风险之间的关系， 在不同种族和民族之间。

Various forms of chronic distress have been linked with premature aging, and development of cardiometabolic diseases (CMD), which are leading causes of death for older adults. Both chronic distress and CMD conditions are strongly linked with risk of Alzheimer's Disease and Alzheimer's Disease-Related Dementias (AD/ADRD). While metabolic changes affecting vascular health are proposed as a key pathway driving the relationship between chronic distress and major diseases of aging, understanding of molecular mechanisms underlying such metabolic changes is limited. High-throughput technologies permit simultaneous measurement of hundreds of metabolites in plasma (“metabolomics”) and provide a broad picture of an individual’s metabolic profile. In our first funding cycle, we developed and validated a liquid chromatography-tandem mass spectrometry (LC-MS)-based metabolomic score of chronic distress (anxiety and depression), in independent data sets of largely non-Hispanic White women; this score was associated with higher risk of incident CMD. In this renewal, using cutting edge metabolomic and biostatistical approaches along with several additional cohort studies, we propose to extend our initial findings and address the following specific aims: (1) Strengthen our existing chronic distress metabolite-score by adding novel, previously unknown metabolites strongly associated with the distress phenotype, and biochemically identify these validated but unknown metabolites to provide new mechanistic insight; (2) Assess our chronic distress metabolomic score (and its components) in key populations including African-American (AA) and Hispanic men and women and White men, and optimize the score in each population. We will also evaluate associations of the score (and components) with CMD and secondarily AD/ADRD risk in AA men and women, White men, and preliminarily in Hispanic men and women, and (3) Evaluate if chronic distress influences the distress-related metabolite score using causal methods and evaluate the distress-metabolite score as a potential mediator of the relationships of chronic distress with CMD risk and secondarily with AD/ADRD risk. We will achieve our aims by leveraging the robust data resources of five prospective studies: the Jackson Heart Study (n=5,306; 100% AA men and women), the Multi-Ethnic Study of Atherosclerosis (n=6,814; 39% White, 28% AA, 22% Hispanic, 12% Asian-American men and women), the Nurses’ Health Study (NHS; n=121,700, 98% White women), the Women’s Health Initiative (n=161,808 women; 18% non-White), PREDIMED (n=7,447; White men and women). Each cohort has similarly assessed chronic distress, blood metabolomic profiles, relevant covariates, CMD and dementia risk outcomes over up to 20 years of follow-up. NHS and MESA also have genetics data and repeated metabolomics measures. This work will extend our understanding of biologic pathways underlying chronic distress and their association with subsequent CMD and dementia risk among both women and men and across racial and ethnic groups.