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

项目摘要/摘要 随着正常衰老，学习、巩固和检索信息的能力开始下降，这是一个主要风险 阿尔茨海默病(AD)和痴呆症的致病因素。美国人口普查机构发布的2012年全国预测报告 统计局表示，到2050年，美国65岁以上的人口将约为8400万，这将 占预计美国总人口的21%。同样在美国，目前65岁以上的人中有16%-20%是 被预测为认知受损的。了解与年龄相关的认知衰退的机制可能有助于 并导致发现有效的治疗方法来改善AD的认知功能。 基因组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相关的认知功能下降至关重要。近期 研究还表明，表观基因组，特别是DNA甲基化，可以用来 区分实际年龄和生物年龄。即，个人的确切年龄(按时间顺序排列的年龄) 相对于一个人的表观年龄(生物年龄)。DNA模式的精确收集 在不同的组织类型中用来区分这些差异的甲基化被称为表观遗传时钟。 虽然已经从混合组织和整个大脑区域发表了几个表观遗传学时钟，但在 是否没有研究确定记忆所必需的大脑区域中的表观遗传时钟，并确定 时钟预测年龄受损或年龄未受损认知能力，这将代表 一项重大的理念和技术创新。在这项建议中，我们的目标是确定表观遗传时钟在 海马体，参与学习和记忆的大脑主要区域，随着年龄的增长开始衰退 并因AD病理而进一步受损。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(使用简化的亚硫酸氢盐测序) 2个月龄和20个月龄的雄性和雌性C57BL/6小鼠的海马区 到达一个表观遗传时钟。在目标1中，我们建议在野生型中鉴定一个海马表遗传时钟 雄鼠和雌鼠的寿命，并确定表观遗传时钟是如何在上下文中改变的 使用5xFAD小鼠模型进行AD的实验研究。在目标2中，我们建议确定表观遗传时钟可以预测 野生型动物的年龄受损与年龄未受损的认知表现，以及时钟是否可以 区分5xFAD动物的恢复力和认知能力下降的易感性。

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.