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脏代谢的发展有关 疾病(CMD)，这是老年人死亡的主要原因。慢性苦恼和慢性精神疾病 与阿尔茨海默病和阿尔茨海默病相关痴呆(AD/ADRD)的风险密切相关。 而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 在慢性忧郁症和主要衰老疾病之间，了解 这种新陈代谢变化是有限的。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”)，并提供了一个人代谢的概貌 侧写。在我们的第一个资金周期中，我们开发并验证了一种高效液相色谱-串联质谱仪 基于光谱(LC-MS)的慢性苦恼(焦虑和抑郁)代谢学评分 主要是非西班牙裔白人女性的数据集；这一得分与发生CMD的风险较高相关。在……里面 使用尖端代谢学和生物统计学方法以及几个额外的队列进行更新 我们建议扩大初步研究结果，并针对以下具体目标：(1)加强我们的 现有慢性窘迫代谢物-强烈添加新的、以前未知的代谢物进行评分 与窘迫表型相关，并生化鉴定这些有效但未知的代谢物以 提供新的机制洞察力；(2)评估我们的慢性痛苦代谢评分(及其组件) 主要人群包括非洲裔美国人(AA)和西班牙裔男性和女性以及白人男性，并优化 每个种群中的分数。我们还将评估分数(和组成部分)与CMD和 在AA男性和女性、白人男性中其次是AD/ADRD风险，初步在西班牙裔男性和女性中， 以及(3)使用因果方法评估慢性苦恼是否影响苦恼相关代谢产物得分 评估苦恼代谢物评分作为慢性苦恼与慢性忧郁症关系的潜在介体 风险，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=6814；39%白人，28%AA，22%西班牙裔，12%亚裔美国男性和 护士健康研究(NHS；n=121,700，98%白人妇女)，妇女健康倡议 (n=161,808名女性；18%非白人)，PREDIMED(n=7,447名；白人男性和女性)。每个队列都有 评估相似的慢性痛苦、血液代谢特征、相关协变量、慢性精神疾病和痴呆症风险 在长达20年的随访中取得的结果。NHS和MESA也有遗传学数据和重复 新陈代谢组学措施。这项工作将扩大我们对慢性阻塞性肺疾病的生物学途径的理解 女性和男性的痛苦及其与随后的CMD和痴呆症风险的相关性 跨越种族和民族群体。

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.