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.

我们建议验证和导出到老化领域 生物衰老：Dunedinpoam4x。该测量对于基本的衰老研究和 测试干预措施是否减慢了一个人的衰老空间。我们在Nia的领导下开始这项工作 R01 AG032282（Belsky等人2015）。在过去的二十年中，我们追踪了19个生物标志物的面板 同年（1972-73）在人群中出生的1,000个人的生理功能 - 代表但尼丁研究。我们的目标是在同一年龄的人中衡量 生物学衰老的变化定义为：逐步，渐进性下降 同样影响多器官系统。我们追踪了心血管，代谢， 通过重复生物标志物在 26、32、38和45岁（保留94％）。这个独一无二的数据集的生长曲线建模 产生了一个年龄的度量标准 正在衰老（Elliott等人自然衰老，2021年）。工作的下一个阶段将机器学习应用于 参与者的45岁全基因组DNA甲基化数据，培训算法 标准得出一个称为dunedinpoam4x的分数（老化甲基化的速度，4波）。这个技术 进步意味着一个人的衰老速度只能从一个血液样本中估算出来，并且 可以将指标导出到具有血液甲基化数据的任何研究样本。以前我们有 报告的验证检查对Dunedinpoam的初步版本，最高38岁，表明该检查 衰老得分的甲基化空间更快的人随后经历了先进的面部 年龄，认知和身体机能，慢性疾病和早期死亡率下降（Belsky等。 Elife 2020）。我们的目的建议对dunedinpoam4x的系统除外验证评估 19个以上的数据集，测试其在老年人，年轻人，种族/种族中的适用性以及几个 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。我们的总体 假设是Dunedinpoam4x将比生物学衰老更精确地表征 时钟，这样做将带来添加的信息值，而不是时钟以上。除了目标 - 具体出版物，我们计划最终的合成出版物。我们将把基础科学家和 干预研究人员是一个可靠，有效的开放访问测量 老化。