The role of toxic and essential metal mixtures, and co-exposures to social stressors, in cognitive aging, mild cognitive impairment, and novel epigenetic age biomarkers: The Baltimore Memory Study

有毒和必需金属混合物以及共同暴露于社会压力源在认知衰老、轻度认知障碍和新型表观遗传年龄生物标志物中的作用：巴尔的摩记忆研究

• 批准号: 10215906
• 负责人: Katherine A Moon
• 金额: $ 9.82万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-13 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215906
• 关键词: Acceleration; Address; Adrenal Glands; Advisory Committees; Age; Aging; Algorithms; Area; Award; Baltimore; Behavioral; Biological; Biological Markers; Biological Specimen Banks; Blood; Brain; Cadmium; Cardiovascular system; Chemicals; Chronic; Chronic stress; Chronology; Clinic Visits; Cognition; Cognitive; Cognitive aging; Communities; DNA Methylation; Data; Dementia; Discrimination; Disease; Elderly; Enrollment; Environmental Exposure; Environmental Hazards; Environmental Risk Factor; Epidemiology; Epigenetic Process; Ethnic Origin; Exposure to; Factor Analysis; Fluorescence; Functional disorder; Goals; Health; Hydrocortisone; Hypothalamic structure; Impaired cognition; Individual; Intervention; Joints; Lead; Light; Link; Longitudinal cohort study; Manganese; Measurement; Measures; Memory; Mentors; Mercury; Metabolic; Metabolic Pathway; Metals; Methodology; Mission; Modeling; Modification; Moon; National Institute of Environmental Health Sciences; Neighborhoods; Neuraxis; Neurodegenerative Disorders; Neurotoxins; Older Population; Outcome; Participant; Pathway interactions; Persons; Phase; Physiological; Pituitary Gland; Policies; Population; Poverty; Race; Research Personnel; Residual state; Risk; Risk Factors; Roentgen Rays; Role; Saliva; Sampling; Socioeconomic Status; Statistical Models; Toxic Environmental Substances; Trace Elements; Training; Urine; Visit; base; bone lead; causal model; cognitive function; disability; disparity elimination; environmental stressor; epidemiology study; epigenetic marker; epigenomics; experience; genome-wide; hazard; health disparity; hypothalamic-pituitary-adrenal axis; lead dose; mild cognitive impairment; modifiable risk; mortality; novel; prevent; psychosocial; public health priorities; social factors; social stressor; stressor; theories; tibia; toxic metal

PROJECT SUMMARY Environmental toxicants are understudied modifiable risk factors for cognitive decline and dementia. Toxic metals, and some essential trace elements, are well-known neurotoxicants and have been linked to cognitive decline. Evaluating the joint actions of environmental exposures may elucidate shared physiologic pathways and may inform policy. Populations with documented health disparities may be especially vulnerable to such pathways due to higher cumulative exposure to environmental hazards and social stressors like poverty, discrimination, or unsafe neighborhoods. Growing evidence suggests that novel epigenetic markers of DNA methylation age predict a host of aging-related outcomes. Few studies have examined whether environmental toxicants, individually or as a mixture, predict DNA methylation age acceleration. To address these gaps, the Candidate proposes new aims in the Baltimore Memory Study, a study of cognitive and cardiovascular aging in 50- to 70-year-old residents of Baltimore, with diversity in race/ethnicity and socioeconomic status. The overall objective of this proposal is to determine whether co-exposures to environmental toxicants and contextual (neighborhood) stressors are linked to cognitive function, mild cognitive impairment, novel epigenetic biomarkers. In the K99 phase, Dr. Moon will take advantage of existing bone lead biomarkers and chronic stress measures to estimate whether the causal association of lead on longitudinal cognitive function (Aim 1) or mild cognitive impairment (Aim 2) is modified by either a theory-based scale of neighborhood psychosocial hazards or hypothalamic-pituitary-adrenal-axis dysfunction, measured by saliva cortisol. To complete these aims and prepare for independence, Dr. Moon will train in four methodologic areas: cognitive aging epidemiology, mixture and causal inference models, co-exposures to social stressors, and epigenetics through formal coursework and mentoring. These training goals will be completed under the guidance of a strong mentoring and advisory team (Drs. Schwartz, Buckley, Gross, Dean, and Ladd-Acosta). This Pathway in Independence Award is critical to achieving Dr. Moon's long-term goal of becoming an independent investigator with expertise on the environmental determinants of aging-related disease, particularly cognitive aging outcomes, and evaluating how co-occurring social stressors contribute to health disparities. In the R00 phase, Dr. Moon will take advantage of stored biospecimens, measuring toxic and essential metals in urine and genome-scale DNA methylation in blood. Using this new data, she will determine the independent joint and effects of a mixture of metals on cognitive aging (cognitive function and mild cognitive impairment) (Aim 3) and on DNA methylation age acceleration (Aim 4). The proposed training and aims will provide further evidence that social and environmental factors must be addressed together to eliminate disparities in aging and preliminary data to support an R01 investigating the role of a mixture of metals and chronic stressors on DNA methylation-based biomarkers in aging.

项目概要 环境毒物是认知能力下降和痴呆的可改变危险因素，这一因素正在得到充分研究。有毒的 金属和一些必需的微量元素是众所周知的神经毒物，并且与认知能力有关 衰退。评估环境暴露的联合作用可能会阐明共同的生理途径 并可能为政策提供信息。有记录的健康差异的人群可能特别容易受到这种影响 由于环境危害和贫困等社会压力的累积暴露程度较高， 歧视或不安全的社区。越来越多的证据表明 DNA 的新型表观遗传标记 甲基化年龄可以预测许多与衰老相关的结果。很少有研究探讨环境是否 有毒物质，无论是单独的还是作为混合物，都预示着 DNA 甲基化年龄的加速。为了解决这些差距， 候选人在巴尔的摩记忆研究中提出了新目标，该研究是一项关于认知和心血管衰老的研究 巴尔的摩 50 至 70 岁的居民，具有种族/民族和社会经济地位的多样性。整体 该提案的目的是确定是否同时暴露于环境毒物和背景环境中 （邻里）压力源与认知功能、轻度认知障碍、新的表观遗传有关 生物标志物。在K99阶段，Moon博士将利用现有的骨铅生物标志物和慢性 压力测量来估计铅是否与纵向认知功能存在因果关系（目标 1） 或轻度认知障碍（目标 2）通过基于理论的邻里心理社会量表进行修改 通过唾液皮质醇测量的危害或下丘脑-垂体-肾上腺轴功能障碍。为了完成这些 为了实现独立并为独立做好准备，文博士将在四个方法领域进行培训： 认知衰老 流行病学、混合和因果推理模型、共同暴露于社会压力源以及表观遗传学 正式的课程作业和指导。这些训练目标将在强有力的指导下完成 指导和咨询团队（Schwartz、Buckley、Gross、Dean 和 Ladd-Acosta 博士）。这条途径在 独立奖对于实现文博士成为独立人士的长期目标至关重要 具有衰老相关疾病环境决定因素（特别是认知能力）方面专业知识的研究者 老龄化结果，并评估同时发生的社会压力如何导致健康差异。在R00 阶段，Moon 博士将利用储存的生物样本，测量尿液中的有毒金属和必需金属 以及血液中基因组规模的 DNA 甲基化。使用这些新数据，她将确定独立联合 以及金属混合物对认知衰老（认知功能和轻度认知障碍）的影响（目标 3） 以及 DNA 甲基化年龄加速（目标 4）。拟议的培训和目标将进一步提供 有证据表明，必须共同解决社会和环境因素，以消除老龄化差异 以及支持 R01 的初步数据，调查金属和慢性压力源的混合物对 基于 DNA 甲基化的衰老生物标志物。