Development of an epigenetic clock that predicts age-impaired or age-unimpaired cognitive performance

项目概要/摘要 学习、巩固和检索信息的能力开始随着正常的衰老而下降，这是一个主要的风险 阿尔茨海默病（AD）和痴呆症的因素。美国人口普查局2012年国家预测报告 统计局表示，到2050年，美国65岁以上的人口将达到8400万， 占美国总人口的21%。同样在美国，目前65岁以上的人中有16-20%是 被预测为认知受损了解与年龄相关的认知能力下降的机制可能会提供信息， AD相关的痴呆症，并导致发现改善AD认知功能的有效治疗方法。 基因组学和表观基因组学研究以及认知神经表观遗传学研究表明， 表观基因组的改变可能对年龄和AD相关的认知能力下降至关重要。最近 研究还表明，表观基因组，特别是DNA甲基化，可用于 区分生理年龄和生理年龄。也就是说，个人的确切年龄（实足年龄） 相对于个体的表观年龄（生物学年龄）。DNA模式的精确集合 用于在不同组织类型中进行这些区分的甲基化被称为“表观遗传时钟”。 虽然已经发表了几个表观遗传时钟从混合组织和整个大脑区域， 没有研究确定大脑区域中记忆所必需的表观遗传时钟，并确定 该生物钟预测年龄受损或年龄未受损的认知表现的能力， 这是一项重大的概念和技术创新。在这个提议中，我们的目标是确定一个表观遗传时钟， 海马体，一个与学习和记忆有关的主要大脑区域，随着年龄的增长， 并且在AD病理中变得甚至进一步受损。我们的初步数据表明我们有能力 开发DNA甲基化数据分析管道（使用简化代表性亚硫酸氢盐测序）， 2和20个月大的雄性和雌性C57 BL/6小鼠的海马，这为 到达一个表观遗传时钟。在目的1中，我们提出了在野生型海马中鉴定海马表观遗传时钟， 在整个生命周期中的雄性和雌性小鼠，并确定表观遗传时钟是如何改变的， 使用5xFAD小鼠模型的AD。在目标2中，我们提出确定表观遗传时钟可以预测 年龄受损与年龄未受损的野生型动物的认知表现，以及时钟是否可能 在5xFAD动物中区分复原力与对认知下降的易感性。

Project Summary/Abstract The ability to learn, consolidate and retrieve information begins to decline with normal aging, a major risk factor for Alzheimer’s Disease (AD) and dementia. The 2012 National Projections report by the U.S. Census Bureau indicates that in 2050 the population in the U.S. aged 65+ will be approximately 84 million, which will reflect 21% of the predicted U.S. total population. Also in the U.S., 16-20% of current 65+ individuals are predicted to be cognitively impaired. Understanding mechanisms of age-related cognitive decline may inform AD-related dementia and lead to the discovery of effective treatments for improving cognitive function in AD. Genomic and epigenomic studies, as well as cognitive neuroepigenetic studies, have demonstrated that alterations of the epigenome may be critically important to age- and AD-associated cognitive decline. Recent studies have also demonstrated that the epigenome, and DNA methylation in particular, may be used to distinguish chronological age from biological age. That is, the exact age of an individual (chronological age) versus the apparent age of an individual (biological age). The precise collection of patterns of DNA methylation that are used to make these distinctions in different tissue types are called ‘epigenetic clocks’. Although several epigenetic clocks have been published from mixed tissues and whole brain regions, there are no studies identifying an epigenetic clock in a brain region necessary for memory, and determining the ability of that clock to predict age-impaired or age-unimpaired cognitive performance, which would represent a major conceptual and technical innovation. In this proposal, we aim to identify an epigenetic clock in the hippocampus, a major brain region involved in learning and memory, and one that begins to decline with age and becomes even further impaired with AD pathology. Our preliminary data demonstrates our ability to develop a DNA methylation data analysis pipeline (using reduced representation bisulfite sequencing) from the hippocampus of 2 and 20 month old male and female C57BL/6 mice, which established a foundation for arriving at an epigenetic clock. In Aim 1 we proposed to identify a hippocampus epigenetic clock in wildtype male and female mice across the lifespan, and to determine how that epigenetic clock is altered in the context of AD using the 5xFAD mouse model. In Aim 2, we propose to determine the epigenetic clock can predict age-impaired versus age-unimpaired cognitive performance in wild type animals, and whether the clock may distinguish resilience versus susceptibility to cognitive decline in 5xFAD animals.