A Novel Epigenetic Clock for Brain Aging

摘要 衰老的生物标志物对于促进健康寿命的有效研究至关重要。有一个特别紧急的问题 对大脑老化的分子生物标记物的需求；因神经退行性疾病而死亡的人数有所增加 相比之下，心脏病和癌症死亡率的下降。表观遗传失调明显与 脑老化、阿尔茨海默病和其他神经系统疾病。表观时钟生物标记物结合dNaM 选择CpG位点的水平来估计生物年龄；表观遗传时钟强烈预测死亡率，以及 其中几项与神经学结果略有关联。然而，虽然特定的儿科时钟现在已经 是针对年轻群体的生物衰老而开发的，目前还没有针对老年人的时钟 或者把重点放在与衰老有关的机械途径上。我们在这里提出了一个新的表观遗传学时钟，建立了 核糖体DNA甲基化(RDNAm)。Rdna基因座包含基本的、进化上保守的。 衰老机制，rDNAm与年龄的相关性比其他片段更大 基因组产生一个高效和有效的表观遗传时钟生物标记物。在最初的工作中，我们报告了一个 在老鼠血中训练的rDNAm时钟在人类和犬类中得到了很好的校准。因此，rDNA可能代表 一个令人信服的表观遗传调控维度，为既定时钟提供互补优势。 我们建议研究构建大脑老化的rDNAm时钟。事实上，最近对表观遗传时钟的一项审查 建议新开发这种植根于特定组织和途径的特殊时钟，以 推进该领域的研究。建议的目标是利用宗教教团学习和快速记忆以及 老龄化项目(ROSMAP)，有1450个大脑样本(包括血液样本的子集)，以及广泛的 表型数据。在目标1中，我们将记录背外侧前额叶皮质(DLPFC)的rDNAm状态，并训练 一个rDNAm时钟在800个年龄&gt；65岁的标本中，增强了对老化大脑的应用。然后我们将测试 其余650例ROSMAP患者rDNAm脑钟与阿尔茨海默病神经病理特征的关系 DLPFC。在目标2中，我们将在另外两个大脑区域(初级枕叶皮质， 下前颞叶皮质)，并在血液样本中作为更容易获得的组织进行研究。在目标3中，我们 将rDNAm大脑时钟与现有时钟进行对比。影响：我们的重点是高度保守的rDNA基因座 可能改善rDNAm时钟在组织中的应用，同时将rDNA与衰老和神经生物学联系起来 可以增强对大脑健康的应用。提出的AIMS可以产生新的工具来评估大脑年龄、预测 神经退行性疾病的风险，为神经退行性疾病的潜在机制提供了新的见解，以及 确定延缓大脑老化的干预措施。此外，鉴于rDNA在细胞新陈代谢和 随着年龄的增长，我们将为这些队列中的更大规模的研究添加丰富的高维数据。

ABSTRACT Biomarkers of aging are critical to effective research promoting the healthspan. There is a particularly urgent need for molecular biomarkers of brain aging; deaths due to neurodegenerative diseases have increased, in contrast to decreases in heart disease and cancer mortality. Epigenetic dysregulation is clearly implicated in brain aging, Alzheimer dementia, and other neurologic diseases. Epigenetic clock biomarkers combine DNAm levels across select CpG sites to estimate biologic age; epigenetic clocks strongly predict mortality, and several are modestly associated with neurologic outcomes. However, while specific pediatric clocks have now been developed to target biologic aging in younger age groups, no clocks to date target older populations or focus on pathways mechanistically implicated in aging. We propose here a novel epigenetic clock, built on ribosomal DNA methylation (rDNAm). The rDNA locus harbors fundamental, evolutionarily conserved aging mechanisms, and rDNAm has greater association with age than any other segment of the genome - yielding an efficient and effective epigenetic clock biomarker. In initial work, we reported an rDNAm clock trained in mouse blood was well-calibrated in humans and canids. Thus, the rDNA may represent a compelling dimension of epigenetic regulation, providing complementary strengths to established clocks. We propose research constructing a rDNAm clock of brain aging. Indeed, a recent review of epigenetic clocks recommended new development of such specialized clocks, rooted in specific tissues and pathways, to advance research in the field. The proposed Aims utilize the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), with 1450 brain specimens (including a subset with blood samples), and extensive phenotypic data. In Aim 1, we will document rDNAm states in dorsolateral pre-frontal cortex (DLPFC), and train a rDNAm clock in 800 specimens age >65 years, to enhance applications to aging brain. We will then test relations of the rDNAm brain clock to Alzheimer disease neuropathologic traits in the remaining 650 ROSMAP DLPFC. In Aim 2, we will evaluate the rDNAm brain clock in two further brain regions (primary occipital cortex, inferior anterior temporal cortex), and in blood samples as a more accessible tissue for research. In Aim 3, we will contrast the rDNAm brain clock to existing clocks. IMPACT: Our focus on the highly conserved rDNA locus may improve application of the rDNAm clock across tissues, while links of rDNA to aging and neurobiology could enhance applications to brain health. Proposed Aims can yield novel tools to evaluate brain age, predict risk of neurodegenerative diseases, provide new insights into mechanisms underlying neuro-degeneration, and identify interventions to delay brain aging. Additionally, given the centrality of rDNA in cellular metabolism and aging, we will add to a wealth of high-dimensional data for larger research in these Cohorts.