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

项目摘要 环境毒物是认知能力下降和痴呆症的未充分研究的可改变的危险因素。有毒 金属和一些必需的微量元素是众所周知的神经毒物，并与认知有关。 下降评估环境暴露的联合作用可以阐明共同的生理途径 并且可以告知政策。有记录的健康差异的人群可能特别容易受到这种影响。 路径由于更高的累积暴露于环境危害和社会压力，如贫困， 歧视或不安全的社区。越来越多的证据表明，新的DNA表观遗传标记 甲基化年龄预测了一系列与衰老相关的结果。很少有研究探讨环境是否 毒物，单独或作为混合物，预测DNA甲基化年龄加速。为了弥补这些差距， 候选人在巴尔的摩记忆研究中提出了新的目标，该研究是一项关于认知和心血管衰老的研究， 50-到70岁的巴尔的摩居民，在种族/民族和社会经济地位的多样性。整体 本提案的目的是确定是否共同暴露于环境毒物和环境 （邻里）压力源与认知功能、轻度认知障碍、新型表观遗传有关 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 压力措施，以估计是否因果关系的铅对纵向认知功能（目标1） 或轻度认知障碍（目标2）是由一个基于理论的规模邻里心理社会 危险或下丘脑-垂体-肾上腺轴功能障碍，通过唾液皮质醇测量。完成这些 为了实现目标并为独立做好准备，穆恩博士将在四个方法论领域进行培训：认知老化 流行病学，混合和因果推理模型，共同暴露于社会压力，和表观遗传学通过 正式的课程和指导。这些培训目标将在一个强有力的指导下完成 指导和咨询团队（施瓦茨博士，巴克利，格罗斯，院长和拉德阿科斯塔）。这条路在 独立奖对于实现Moon博士成为独立人士的长期目标至关重要 具有与衰老有关的疾病的环境决定因素方面的专门知识的调查员，特别是认知 老龄化的结果，并评估共同发生的社会压力如何促成健康差距。在R 00 Moon博士将利用储存的生物样本，测量尿液中的有毒和必需金属 和血液中基因组规模的DNA甲基化。利用这些新数据，她将确定独立关节 以及金属混合物对认知老化（认知功能和轻度认知障碍）的影响（目标3） 和DNA甲基化年龄加速（Aim 4）。拟议的培训和目标将进一步提供 有证据表明，社会和环境因素必须共同解决，以消除老龄化的差距 和初步数据，以支持R 01调查的作用，混合金属和慢性应激源， DNA甲基化为基础的生物标志物在老化。

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.