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.

抽象的 衰老的生物标志物对于促进健康范围的有效研究至关重要。有一个特别紧急的 需要大脑衰老的分子生物标志物；由于神经退行性疾病而导致的死亡增加了 与心脏病和癌症死亡率降低相比。表观遗传失调显然与 大脑衰老，阿尔茨海默氏症痴呆症和其他神经系统疾病。表观遗传钟生物标志物结合了dnam 各个CPG站点的水平以估计生物年龄；表观遗传时钟强烈预测死亡率，并且 几个与神经系统结局谦虚相关。但是，虽然特定的小儿钟现在有 已开发以靶向年轻年龄段的生物衰老，没有时钟到迄今为止较老的人群 或专注于与衰老有关的机械途径。我们在这里提出了一个新颖的表观遗传钟，建造了 在核糖体DNA甲基化（RDNAM）上。 rDNA基因座港口基本，进化保守 与年龄相比 基因组 - 产生有效有效的表观遗传钟生物标志物。在最初的工作中，我们报告了 在人类和犬科动物中，接受了用小鼠血液训练的RDNAM时钟进行了很好的校准。因此，rDNA可能代表 表观遗传调节的令人信服的维度，为已建立的时钟提供了互补的优势。 我们提出了构建大脑衰老的RDNAM时钟的研究。确实，最近对表观遗传时钟的评论 推荐了这种专业时钟的新开发，它植根于特定的组织和途径， 提前研究该领域。拟议的目的利用宗教秩序的研究和匆忙记忆， 衰老项目（Rosmap），有1450个大脑标本（包括带有血液样本的子集），广泛 表型数据。在AIM 1中，我们将记录RDNAM州背侧额外额外皮层（DLPFC）和训练 800个标本年龄> 65岁的RDNAM时钟，以增强对大脑衰老的应用。然后我们将测试 RDNAM脑时钟与阿尔茨海默氏病神经病理性状的关系 DLPFC。在AIM 2中，我们将评估两个进一步的大脑区域的RDNAM脑时钟（原发性枕皮层， 下颞皮层下部），在血液样本中作为更容易获得的研究。在AIM 3中，我们 将将RDNAM脑时钟与现有时钟进行对比。影响：我们关注高度保守的rDNA基因座 可以改善rdnam时钟在组织中的应用，而rDNA与衰老和神经生物学的联系 可以增强对大脑健康的应用。拟议的目标可以产生新的工具来评估脑时代，预测 神经退行性疾病的风险，提供有关神经脱生机制的新见解，并提供 确定延迟大脑衰老的干预措施。此外，鉴于rDNA在细胞代谢中的中心性和 衰老，我们将增加大量的高维数据，以在这些人群中进行更大的研究。