CELLULAR AND MOLECULAR GEROSCIENCE CoBRE

摘要 该项目旨在通过开发衰老生物标志物来推进衰老研究， 基于表观遗传时钟的模型，一种从DNA预测年龄的机器学习模型 任何人体组织中的甲基化变化。我们建议测试这些时钟的关联， 认知和血管病变，以及产生新的时钟设计来预测年龄- 相关功能障碍。我们建议评估表观遗传时钟在临床上的表现， 通过将认知功能和血管认知障碍测量与DNA 甲基化数据。我们的目标是确定表观遗传时钟是否可以作为衰老的生物标志物 使用可接近的组织（血液）来预测与年龄相关的血管和认知功能障碍。要求1 将确定表观遗传时钟预测与年龄相关的血管和 认知障碍的血液样本我们将测试霍瓦特莱文 以及我们自己的表观遗传时钟的“年龄加速”和认知与大脑的功能数据 人体样本的血管健康我们将从先前收集的甲基化数据中生成甲基化数据， 白色血细胞，将与使用剑桥的认知评估配对 神经心理学自动成套测试（CANTAB）的认知测试，脑血管健康 使用经颅多普勒（TCD），功能性近红外光谱（fNIRS），动态视网膜 血管分析和外周血管健康使用流量介导的扩张方法，在大 （超声检查）和小血管（激光散斑对比成像）。我们假设 加速度应与认知和血管功能呈负相关，无论是在中央 循环和外围。这些分析将提供关键证据，以确定 表观遗传时钟可以是大脑老化的临床相关生物标志物。在Aim 2中，我们将 设计新的表观遗传时钟来预测血管和认知障碍， 在一项对公开数据的荟萃分析中，使用相同的 在aim 1中生成的表观遗传数据，我们将训练新的表观遗传时钟， 而不是实际年龄。我们假设表观遗传时钟被训练来预测 血管和认知功能障碍也将能够预测与年龄相关的疾病状态。

ABSTRACT This project aims to advance aging research by developing a biomarker for aging using a model based upon the epigenetic clock, a machine learning model that predicts age from DNA methylation changes in any human tissue. We propose to test these clocks’ association to cognitive and vascular pathologies, as well as to generate new clocks designed to predict age- related dysfunction. We propose to evaluate the performance of epigenetic clocks in clinical samples by correlating cognitive function and vascular-cognitive impairment measures with DNA methylation data. Our goal is to determine if epigenetic clocks can serve as an aging biomarker using accessible tissue (blood) to predict age-related vascular and cognitive dysfunction. Aim 1 of the project will determine the ability of epigenetic clocks to predict age-associated vascular and cognitive impairment from blood samples. We will test the association between Horvath, Levine, and our own epigenetic clocks’ “age acceleration” and functional data on cognition and brain vascular health from human samples. We will generate methylation data from previously collected white blood cells, which will be paired with cognitive assessment using the Cambridge Neuropsychological Test Automated Battery (CANTAB) of cognitive tests, cerebrovascular health using transcranial doppler (TCD), functional near-infrared spectroscopy (fNIRS), dynamic retinal vessel analysis, and peripheral vascular health using the flow mediated dilation approach in large (ultrasonography) and small vessels (laser speckle contrast imaging). We hypothesize that age acceleration should be negatively correlated with cognitive and vascular function both in central circulation and in the periphery. These analyses will provide evidence critical to determining if epigenetic clocks can be a clinically relevant biomarker for aging in the brain. In the Aim 2, we will design new epigenetic clocks to predict vascular and cognitive impairment and evaluate their association to AD and cognitive impairment in a meta-analysis of public data. Using the same epigenetic data generated in aim 1, we will train new epigenetic clocks that predict functional impairment instead of chronological age. We hypothesize that epigenetic clocks trained to predict vascular and cognitive dysfunction will also be able to predict age-related disease status.