Arpawong Thalida Em, Hernandez Belinda, Potter Claire, Leigh Robert J, Klopack Eric T, Hill Claire, Fiorito Giovanni, Smyth Laura J, O'Halloran Aisling M, McGuinness Bernadette, Faul Jessica D, Kenny Rose Anne, McKnight Amy Jayne, Crimmins Eileen M, McCrory Cathal
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA.
The Irish Longitudinal Study On Ageing (TILDA), Department of Medical Gerontology, School of Medicine, Trinity College Dublin, Dublin, Ireland.
Geroscience. 2025 Sep 1. doi: 10.1007/s11357-025-01832-1.
The complexity of epigenetic changes that accompany aging has been distilled into a number of molecular timepieces-termed epigenetic clocks-that characterize the pace of biological aging to differing degrees. Here, we develop and validate a DNA methylation-based Physiological health Age (PhysAge) score, comprised of eight DNA methylation surrogates to represent multi-system physiology and developed from commonly measured clinical biomarkers: CRP, peak flow, pulse pressure, HDL-cholesterol, Hba1c, waist-to-height ratio (WHR), cystatin C, and dehydroepianrosterone sulphate (DHEAS). We use data from the population-representative US Health and Retirement Study (HRS), split into a training (n = 1589) and test sample (n = 1588) and corroborate findings in two independent cohorts: The Irish Longitudinal Study of Aging (TILDA; n = 488) and the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA; n = 1830). PhysAge and the predominant second-generation epigenetic clocks, PhenoAge, GrimAge2, and DunedinPACE, were tested for their prediction of mortality and multiple age-related clinical measures (i.e., grip strength, gait speed, cognitive function, disability, frailty). PhysAge was comparable to extant clocks in predicting health measures and was indistinguishable from GrimAge2 in predicting mortality, despite not being trained on mortality. Moreover, the eight individual surrogates comprising PhysAge predicted health outcomes better than the measured values in many instances. The established clinical relevance of the biomarkers from which surrogates were derived opens up new opportunities for cross-study and cross-country comparisons of population health. Findings suggest that the DNA methylation PhysAge can be leveraged as a single biomarker to represent multiple physiological systems and offers utility in the context of clinical monitoring.
伴随衰老出现的表观遗传变化的复杂性已被提炼为一些分子时钟——即表观遗传时钟——这些时钟在不同程度上表征了生物衰老的速度。在此，我们开发并验证了一种基于DNA甲基化的生理健康年龄（PhysAge）评分，它由八个DNA甲基化替代指标组成，用于代表多系统生理学，并从常见的临床生物标志物中衍生而来：C反应蛋白（CRP）、峰值流量、脉压、高密度脂蛋白胆固醇、糖化血红蛋白（Hba1c）、腰高比（WHR）、胱抑素C和硫酸脱氢表雄酮（DHEAS）。我们使用来自具有人群代表性的美国健康与退休研究（HRS）的数据，将其分为训练样本（n = 1589）和测试样本（n = 1588），并在两个独立队列中证实了研究结果：爱尔兰纵向衰老研究（TILDA；n = 488）和北爱尔兰纵向衰老队列研究（NICOLA；n = 1830）。对PhysAge以及主要的第二代表观遗传时钟PhenoAge、GrimAge2和达尼丁PACE进行了测试，以评估它们对死亡率和多种与年龄相关的临床指标（即握力、步速、认知功能、残疾、衰弱）的预测能力。在预测健康指标方面，PhysAge与现有时钟相当，在预测死亡率方面与GrimAge2难以区分，尽管它并非基于死亡率进行训练。此外，在许多情况下，组成PhysAge的八个个体替代指标比测量值能更好地预测健康结果。替代指标所源自的生物标志物已确立的临床相关性为人群健康的跨研究和跨国比较开辟了新机会。研究结果表明，DNA甲基化PhysAge可作为一种单一生物标志物来代表多个生理系统，并在临床监测中具有实用价值。
