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

基本信息

批准号：
10630306
负责人：
AVSHALOM CASPI
金额：
$ 74.42万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10630306
关键词：
Acceleration Affect African American Age Aging Alzheimer&apos 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 Population 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 Reporting Research Research Personnel Sampling Scientist Scotland System Testing Therapeutic Training Validation Variant Weather Work aged aging brain algorithm training 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 population racial prejudice response sex smoking cessation theories tool whole genome

项目摘要

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衰老：DunedinPoAm4x 该测量对于基础衰老研究和也很有用。测试干预措施是否减缓了人的衰老速度我们在 NIA 的领导下开始了这项工作。 R01 AG032282（Belsky et al 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年）出生的1000人的生理功能- 但尼丁代表性研究的目标是测量相同年龄的人，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 26、32、38 和 45 岁（94% 的保留率）这一独一无二的数据集的生长曲线建模。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老化（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。意味着一个人的衰老进程可以仅通过一个血液样本来估计，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。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，2016）。 eLife 2020）我们的目标提出了对 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每个目标还将测试我们现有的主要甲基化时钟以进行比较。假设 DunedinPoAm4x 将比时钟，这样做除了目标之外还会带来额外的信息价值。具体出版物，我们计划向基础科学家和专家提供最终的综合出版物。干预研究人员，一种可靠、有效、开放的方式来衡量一个人的进展速度老化。