A Novel Epigenetic Clock for Brain Aging

一种新的大脑衰老表观遗传时钟

• 批准号: 10296057
• 负责人: FRANCINE GRODSTEIN
• 金额: $ 95万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10296057
• 关键词: Age; Aging; Alzheimer' s Disease; Anterior; Autopsy; Biological; Biological Aging; Biological Markers; Blood; Blood specimen; Brain; Brain Pathology; Brain region; Cessation of life; Childhood; Chronology; Clinical; DNA Methylation; Data; Dementia; Development; Dimensions; Disease; Epigenetic Process; Felis catus; Genome; Genomics; Heart Diseases; Human; Inferior; Intervention; Link; Malignant Neoplasms; Memory; Metabolism; Methods; Methylation; Mus; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurological outcome; Neurons; Occipital lobe; Older Population; Oranges; Participant; Pathway interactions; Plant Roots; Prefrontal Cortex; Publishing; Reporting; Research; Ribosomal DNA; Risk; Severities; Site; Specimen; Temporal Lobe; Testing; Text; Tissues; Training; Translating; Variant; Work; age group; aging brain; base; bisulfite sequencing; brain health; brain tissue; cohort; disorder risk; epigenetic regulation; healthspan; improved; insight; internal control; molecular marker; mortality; multidimensional data; nervous system disorder; neuropathology; novel; phenotypic data; religious order study; tool; trait

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.

摘要 衰老的生物标志物是促进健康寿命的有效研究的关键。有一个特别紧急的 需要大脑老化的分子生物标志物;由于神经退行性疾病导致的死亡增加， 与心脏病和癌症死亡率的下降形成对比。表观遗传失调显然与 脑老化、阿尔茨海默痴呆症和其他神经系统疾病。表观遗传时钟生物标志物联合收割机DNA m 选择CpG位点的水平来估计生物学年龄;表观遗传时钟强烈预测死亡率， 有几种与神经学结果适度相关。然而，虽然现在有特定的儿科时钟， 针对较年轻年龄组的生物老化而开发，但迄今为止还没有针对老年人群的时钟 或者专注于衰老的机制。我们在这里提出了一种新的表观遗传时钟， 核糖体DNA甲基化（rDNAm）。rDNA位点具有基本的，进化上保守的 衰老机制，rDNAm与年龄的相关性比其他任何部分都要大。 基因组-产生高效和有效的表观遗传时钟生物标志物。在最初的工作中，我们报告了 在小鼠血液中训练的rDNAm时钟在人类和犬科动物中得到良好校准。因此，rDNA可以代表 表观遗传调控的一个引人注目的方面，为既定的时钟提供互补的力量。 我们建议研究构建一个大脑衰老的rDNAm时钟。事实上，最近一项关于表观遗传时钟的综述 建议开发这种专门的时钟，植根于特定的组织和途径， 该领域的先进研究。拟议的目标利用宗教秩序研究和匆忙的记忆， 老龄化项目（ROSMAP），1450个大脑标本（包括血液样本的子集），和广泛的 表型数据在目标1中，我们将记录背外侧前额叶皮层（DLPFC）中的rDNAm状态，并训练 一个rDNAm时钟在800个年龄>65岁的标本中，以增强对衰老大脑的应用。然后我们将测试 剩余650例ROSMAP中rDNAm脑时钟与阿尔茨海默病神经病理学特征的关系 DLPFC。在目标2中，我们将评估另外两个大脑区域（初级枕叶皮质， 下前颞叶皮层），并在血液样本中作为更容易接近的组织进行研究。在目标3中，我们 将rDNAm大脑时钟与现有时钟进行对比。影响：我们对高度保守的rDNA位点的关注 可能会改善rDNAm时钟在组织中的应用，而rDNAm与衰老和神经生物学的联系 可以增强对大脑健康的应用。提出的目标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新的见解， 确定延缓大脑衰老的干预措施。此外，考虑到rDNA在细胞代谢中的中心地位， 老龄化，我们将为这些队列的更大研究增加丰富的高维数据。