Validating a 3rd-generation methylation measure of accelerated aging: DunedinPoAm4x

验证加速衰老的第三代甲基化测量方法：DunedinPoAm4x

• 批准号: 10426479
• 负责人: AVSHALOM CASPI
• 金额: $ 76.59万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10426479
• 关键词: Affect; African American; Age; Aging; Alzheimer' s disease related dementia; Benchmarking; Biological; Biological Aging; Biological Markers; Biology of Aging; Blood; Blood specimen; Brain; Cardiovascular system; Chronic Disease; Chronology; Clinical Trials; Consensus; Country; DNA Methylation; Data; Data Set; Dementia; Dental; Diagnosis; Diagnostic; Disease; Elderly; Ethnic group; Evaluation; Face; Funding; Gene Expression; Generations; Genes; Genetic; Genetic Variation; Genetic study; Genomic Segment; Geroscience; Goals; Growth; Health and Retirement Study; Health behavior change; Hepatic; Human; Immune; Impaired cognition; Individual; Intake; Intervention; Justice; Kidney; Life Style; Longevity; Lung; Machine Learning; Magnetic Resonance Imaging; Measures; Mendelian randomization; Metabolic; Methods; Methylation; Modeling; Nature; Onset of illness; Outcome; Outcome Measure; Participant; Persons; Phenotype; Physical Function; Physical activity; Physiological; Population; Proxy; Psychosocial Deprivation; Publications; Race; Reporting; Research; Research Personnel; Sampling; Scientist; Scotland; System; Testing; Therapeutic; Training; Validation; Variant; Weather; Work; aged; aging brain; algorithm training; base; biomarker panel; body system; brain magnetic resonance imaging; cognitive function; cohort; design; experience; follow-up; frailty; functional decline; genome wide association study; genome-wide; health disparity; healthy aging; immune function; member; mild cognitive impairment; mortality; novel; optimism; polygenic risk score; prospective; psychologic; racial prejudice; response; sex; smoking cessation; theories; tool; whole genome

We propose to validate and export to the aging field a novel tool to measure a person’s pace of biological aging: DunedinPoAm4x. The measure will be useful for basic aging research and also for testing whether an intervention has slowed a person’s pace of aging. We began this work under NIA R01 AG032282 (Belsky et al PNAS 2015). Over two decades, we tracked a 19-biomarker panel of the physiological functions of 1,000 individuals born the same year (1972-73) in the population- representative Dunedin Study. Our goal has been to measure, in people the same chronological age, variation in biological aging defined per geroscience theory as: gradual, progressive decline simultaneously affecting multiple organ systems. We tracked declines in the cardiovascular, metabolic, pulmonary, renal, dental, hepatic, and immune functions of participants by repeating biomarkers at ages 26, 32, 38 and 45 years (94% retention). Growth-curve modelling of this one-of-a-kind dataset yielded a pace-of-aging metric that quantified how slowly or rapidly each participant in our cohort had been aging (Elliott et al Nature Aging, 2021). The next stage of the work applied machine-learning to participants’ age-45 whole-genome DNA methylation data, training an algorithm on the pace-of-aging metric to derive a score called DunedinPoAm4x (Pace of Aging methylation, 4 waves). This technical advance means that a person’s pace of aging can be estimated from just a single blood sample, and the metric can be exported to any research sample that has blood methylation data. Previously we had reported validation checks on a preliminary version of DunedinPoAm, up to age 38, showing that people who had faster methylation pace of aging scores subsequently experienced advanced facial age, declines in cognitive and physical functioning, chronic diseases, and early mortality (Belsky et al eLife 2020). Our Aims propose a systematic out-of-sample validation evaluation of DunedinPoAm4x in 19+ data sets, testing its applicability in older adults, young people, race/ethnic groups, and several countries. Each Aim will also test existing leading methylation clocks for comparison. Our overarching hypothesis is that DunedinPoAm4x will characterize biological aging with greater precision than the clocks, and in so doing will bring added information value over and above the clocks. In addition to aim- specific publications, we plan a final, synthesis publication. We will deliver, to basic scientists and intervention researchers, a reliable, valid, open-access measure of how rapidly a person has been aging.

我们建议验证并向老龄化领域输出一种新工具来衡量一个人的衰老速度 生物老化：DunedinPoAm4x。该措施将有助于基础衰老研究以及 测试干预措施是否减缓了一个人的衰老速度。我们在 NIA 的领导下开始了这项工作 R01 AG032282（Belsky 等人 PNAS 2015）。二十年来，我们追踪了 19 个生物标志物组 人口中同年（1972-73）出生的1000人的生理功能- 但尼丁研究的代表性。我们的目标是测量同龄人中， 根据老年科学理论，生物衰老的变化被定义为：逐渐的、进行性的衰退 同时影响多个器官系统。我们追踪了心血管、代谢、 通过重复生物标志物来评估参与者的肺、肾、牙科、肝和免疫功能 年龄分别为 26、32、38 和 45 岁（94% 保留率）。这一独一无二的数据集的增长曲线建模 得出了一个衰老速度指标，该指标量化了我们队列中每个参与者的衰老速度有多慢或快 一直在衰老（Elliott 等 Nature Aging，2021）。下一阶段的工作将机器学习应用于 参与者 45 岁的全基因组 DNA 甲基化数据，训练衰老速度算法 指标得出称为 DunedinPoAm4x（老化甲基化速度，4 波）的分数。这项技术 先进意味着只需一个血液样本就可以估计一个人的衰老速度，并且 该指标可以导出到任何具有血液甲基化数据的研究样本。以前我们有 报告对 DunedinPoAm 的初步版本进行了验证检查，年龄可达 38 岁，表明 衰老分数甲基化速度较快的人随后会经历高级面部护理 年龄、认知和身体功能下降、慢性疾病和过早死亡（Belsky 等 埃莱夫2020）。我们的目标提出对 DunedinPoAm4x 进行系统的样本外验证评估 超过 19 个数据集，测试其在老年人、年轻人、种族/族裔群体和多个群体中的适用性 国家。每个目标还将测试现有的领先甲基化时钟以进行比较。我们的首要任务 假设 DunedinPoAm4x 将比 时钟，这样做将为时钟带来额外的信息价值。除了目标之外—— 具体出版物，我们计划最终的综合出版物。我们将向基础科学家和 干预研究人员，一种可靠、有效、开放的方法来衡量一个人的进展速度 老化。