Epigenetic Age Acceleration as a Biomarker of Early Life Adversity and Mid-life Cognitive Function

表观遗传年龄加速作为早年逆境和中年认知功能的生物标志物

• 批准号: 10221570
• 负责人: Chad Shenk
• 金额: $ 34.72万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221570
• 关键词: 16 year old; Acceleration; Adolescence; Adult; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; Biological; Biological Markers; Biological Models; Blood specimen; Cells; Child; Child Sexual Abuse; Childhood; Cognitive; Cognitive aging; Communities; Cytosine; DNA; DNA Methylation; Data; Data Collection; Detection; Early Diagnosis; Elderly; Enrollment; Epigenetic Process; Episodic memory; Event; Exposure to; Female; Glucocorticoids; Growth and Development function; Guanine; Health; Hydrocortisone; Impaired cognition; Impairment; Individual; Intervention; Language; Life; Liquid substance; Long-Term Effects; Longevity; Measures; Mediating; Mediation; Modeling; Molecular; Molecular Analysis; Morbidity - disease rate; National Institute on Aging; Neurodegenerative Disorders; Onset of illness; Performance; Physiological; Precision therapeutics; Prevention; Prospective cohort study; Public Health; Recommendation; Reproducibility; Rest; Risk; Risk Factors; Sampling; Science; Short-Term Memory; Site; Socioeconomic Status; Specific qualifier value; Specificity; Statistical Models; Stress; Stressful Event; System; Testing; Theoretical model; Time; Variant; Whole Blood; cognitive ability; cognitive function; cohort; demographics; design; early detection biomarkers; early life adversity; executive function; experience; genome-wide; human tissue; improved; indexing; methylome; middle age; mortality; novel marker; performance based measurement; physical conditioning; polygenic risk score; predictive modeling; prevent; prospective; psychologic; young adult

ABSTRACT Early life adversity affects two-thirds of all children in the U.S. and can have a lasting impact on healthy cognitive aging, interfering with the acquisition of cognitive abilities in early life and leading to earlier, steeper declines in cognitive function at mid-life. Theoretical models specify that early life adversity alters biological stress-mediating systems underlying broad domains of cognitive health. The biological effects of early life adversity can therefore serve as highly novel biomarkers with the unique advantage of being detected prior to cognitive impairment. Identifying biomarkers at mid-life, prior to the onset of cognitive impairment or even neurodegenerative diseases such as Alzheimer's Disease and related dementias, can provide actionable information to improve early detection and efforts at delaying, reversing, or preventing these conditions in late- life. This proposal will examine whether early life adversity alters a novel biomarker of cognitive function at mid- life, epigenetic age, an index of the biological age of human tissues and cells derived from DNA methylation and predictive of cognitive impairment in late-life. Existing data and biospecimens will be used to examine the impact of early life adversity on epigenetic age and its relation to cognitive function at mid-life in the Female Growth and Development Study (N=173; Mage=39.47), a 30-year prospective cohort study of the impact of child sexual abuse. Active data collection with the Female Growth and Development Study is underway and examining the impact of child sexual abuse on cognitive function using well-established, performance-based measures of working memory, inhibitory control, fluid reasoning, and receptive language. The current application would capitalize on this opportunity by advancing comprehensive biological models for how child sexual abuse is embedded in the methylome to affect cognitive function at mid-life. DNA and genome-wide variation in DNA methylation will be characterized through whole blood. DNA methylation at 353 cytosine- guanine sites across the methylome will be used to quantify epigenetic age and examine its relation with child sexual abuse. Mediation models will test whether glucocorticoid remodeling occurring in the sixteen years following child sexual abuse explains accelerations in epigenetic age at mid-life. Variably methylated regions of the methylome affected by child sexual abuse will also be examined to identify regions that have the strongest risk and protective relations with cognitive function at mid-life. Epigenetic age and other established risks, including a cognitive function polygenic risk score, educational attainment, socioeconomic status, and lifetime exposure to stressful events, will be included in statistical models to examine the increased predictive power gained from these molecular analyses of cognitive function beyond known risks. Following recommendations by the National Institute on Aging, this proposal will test epigenetic age as a unique biomarker of cognitive function at mid-life following early life adversity to identify those at greatest risk for cognitive impairment and decline in late-life.

摘要 早期生活逆境影响了美国三分之二的儿童，并可能对健康产生持久的影响。 认知老化，干扰早期认知能力的获得，并导致更早，更陡峭的 中年认知功能下降理论模型表明，早期生活的逆境会改变生物学特性， 压力调节系统是认知健康的广泛领域的基础。早期生命的生物学效应 因此，逆境可以作为高度新颖的生物标志物，其独特的优势是在逆境之前被检测到。 认知障碍在中年、认知障碍发作之前， 神经退行性疾病，如阿尔茨海默病和相关的痴呆症，可以提供可操作的 信息，以改善早期发现和努力延迟，扭转或预防这些条件在后期- 生活这项提案将研究早期生活的逆境是否会改变中期认知功能的一种新的生物标志物。 寿命，表观遗传年龄，由DNA甲基化衍生的人体组织和细胞的生物学年龄指数 并预示着晚年的认知障碍。现有的数据和生物标本将用于检查 早期生活逆境对女性表观遗传年龄的影响及其与中年认知功能的关系 生长发育研究（N=173;法师=39.47），一项为期30年的前瞻性队列研究，旨在评估 性虐待正在积极收集女性生长和发育研究的数据， 研究儿童性虐待对认知功能的影响， 工作记忆、抑制控制、流体推理和接受性语言的测量。当前 应用程序将利用这一机会，推进全面的生物模型，为儿童如何 性虐待嵌入在甲基化基因组中，影响中年人的认知功能。DNA和全基因组 DNA甲基化的变化将通过全血来表征。DNA甲基化在353胞嘧啶- 甲基化组中的鸟嘌呤位点将用于量化表观遗传年龄，并研究其与儿童年龄的关系。 性虐待调解模型将测试是否糖皮质激素重塑发生在十六年 儿童遭受性虐待后，中年人的表观遗传年龄加快。可变甲基化区域 受儿童性虐待影响的甲基化组也将被检查，以确定具有最强的 与中年认知功能的风险和保护关系。表观遗传年龄和其他已确定的风险， 包括认知功能多基因风险评分、教育程度、社会经济地位和寿命 暴露于压力事件，将被纳入统计模型，以检查增加的预测能力 从这些认知功能的分子分析中获得了超出已知风险的信息。以下建议 这项提案将测试表观遗传年龄作为认知能力的独特生物标志物。 在经历早期生活逆境后的中年时期发挥作用，以确定那些认知障碍风险最大的人， 晚年的衰落