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

我们建议验证和出口到老龄化领域的一种新的工具来衡量一个人的步伐， 生物老化：DunedinPoAm4x。这一措施将有助于基础老龄化研究， 测试一种干预措施是否减缓了一个人的衰老速度。我们在NIA下开始这项工作 R01AG032282（Belsky等人PNAS 2015）。二十多年来，我们追踪了19种生物标志物， 1972 - 1973年出生的1,000个人的生理功能， 代表性达尼丁研究。我们的目标是测量，在相同实际年龄的人中， 根据老年科学理论，生物衰老的变化定义为：逐渐的，渐进的衰退 同时影响多个器官系统我们追踪了心血管，代谢， 肺，肾，牙齿，肝脏和免疫功能的参与者，通过重复生物标志物， 年龄为26、32、38和45岁（94%保留）。这个独一无二的数据集的增长曲线建模 得出了一个老化速度指标，量化了我们队列中每个参与者的老化速度有多慢或多快。 （Elliott et al Nature Aging，2021）。下一阶段的工作应用机器学习， 参与者45岁的全基因组DNA甲基化数据，训练一种关于衰老速度的算法。 指标，以获得称为DunedinPoAm4x（老化甲基化速度，4波）的评分。本技术 先进意味着一个人的衰老速度可以从一个单一的血液样本估计， 该度量可以输出到具有血液甲基化数据的任何研究样品。以前我们有 报告了对DunedinPoAm初步版本的验证检查，直到38岁，显示 那些甲基化速度更快的人随后经历了高级面部 年龄、认知和身体功能下降、慢性疾病和早期死亡率（Belsky等人 eLife 2020）。我们的目的是提出一个系统的样本外验证评价达尼丁PoAm4x在 19+数据集，测试其在老年人，年轻人，种族/民族群体和几个 国家每个目标还将测试现有的领先甲基化时钟进行比较。我们的总体 假设DunedinPoAm4x将以更高的精度表征生物老化 时钟，并在这样做将带来额外的信息价值超过时钟。除了目标- 具体的出版物，我们计划最后，综合出版物。我们将向基础科学家和 干预研究人员，一个可靠的，有效的，开放的措施，如何迅速一个人已经 衰老

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.