Longitudinal changes in epigenetic clocks predict survival in the InCHIANTI cohort

Pei-Lun Kuo, Ann Zenobia Moore, Toshiko Tanaka, Daniel W. Belsky, Ake Tzu-Hui Lu, Steve Horvath, Stefania Bandinelli, Luigi Ferrucci
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Abstract

Importance: Cross-sectional assessment of epigenetic clocks provides information on the pace of aging. Whether longitudinal acceleration or deceleration of epigenetic clocks over time provides additional mortality prediction is unknown. Objective: To test the independent associations of baseline levels and longitudinal changes in epigenetic clocks with mortality Design: Longitudinal study Setting: InCHIANTI, a population-based study of community dwelling individuals in Tuscany, Italy. Participants: 699 InCHIANTI study participants aged 21-95 years at baseline with longitudinal measurements of DNA methylation. Exposure: Baseline levels and longitudinal changes in seven epigenetic clocks, including two first-generation clocks developed using chronological age for reference (Hannum Clock, Horvath Clock), three second-generation clocks developed using time-to-death for references (DNAmPhenoAge, DNAmGrimAge, DNAmGrimAge Version 2), and two third-generation clocks developed using longitudinal rate of change of multiple phenotypes for reference (DunedinPOAm_38, DunedinPACE). Main Outcomes and Measures: Mortality was the primary outcome. Cox regression was used to estimate independent associations of baseline and longitudinal changes in epigenetic clocks with mortality. Results: Adjusting for age, sex, study sites, and epigenetic clock at the baseline, longitudinal changes of the following epigenetic clocks were associated with mortality: Hannum clock (aHR = 1.14, 95% CI:[1.03, 1.26]), DNAmPhenoAge (aHR = 1.23, 95% CI: [1.10,1.37]), DNAmGrimAge (aHR = 1.13, 95% CI: [1.02,1.26]), DNAmGrimAge Version 2 (aHR = 1.18, 95% CI:[1.06,1.31]), and DunedinPOAm_38 (aHR = 1.15, 95%CI: [1.01,1.30]). Conclusions and Relevance: Our findings confirm that epigenetic clocks capture a dimension of health that is predictive of mortality and add the notion that time changes of epigenetic age reflect changes in health that additionally and independently contribute to mortality prediction. Future studies should test whether interventions that slow down the rate of epigenetic aging are associated with longer healthspan and lifespan.
表观遗传时钟的纵向变化可预测 InCHIANTI 队列的存活率
重要性:表观遗传时钟的横向评估提供了有关衰老速度的信息。至于表观遗传时钟随时间的纵向加速或减速是否能提供更多的死亡率预测信息,目前还不得而知。目的检验表观遗传时钟的基线水平和纵向变化与死亡率之间的独立关联:纵向研究InCHIANTI 是一项针对意大利托斯卡纳社区居民的人口研究。参与者699 名基线年龄为 21-95 岁的 InCHIANTI 研究参与者,对其 DNA 甲基化进行纵向测量。暴露:七个表观遗传时钟的基线水平和纵向变化,包括两个以计时年龄为参考开发的第一代时钟(Hannum Clock、Horvath Clock)、三个以死亡时间为参考开发的第二代时钟(DNAmPhenoAge、DNAmGrimAge、DNAmGrimAge Version 2)和两个以多种表型的纵向变化率为参考开发的第三代时钟(DunedinPOAm_38、DunedinPACE)。主要结果和测量指标:死亡率是主要结果。采用 Cox 回归估算表观遗传时钟的基线和纵向变化与死亡率的独立关联。结果调整年龄、性别、研究地点和基线表观遗传时钟后,以下表观遗传时钟的纵向变化与死亡率相关:Hannum时钟(aHR = 1.14,95% CI:[1.03, 1.26])、DNAmPhenoAge(aHR = 1.23,95% CI:[1.10,1.37])、DNAmGrimAge(aHR = 1.13,95% CI:[1.02,1.26])、DNAmGrimAge Version 2(aHR = 1.18,95% CI:[1.06,1.31])和 DunedinPOAm_38(aHR = 1.15,95%CI:[1.01,1.30])。结论与相关性:我们的研究结果证实,表观遗传时钟捕捉到了可预测死亡率的一个健康维度,并补充了一个概念,即表观遗传年龄的时间变化反映了健康状况的变化,而健康状况的变化对预测死亡率有额外且独立的贡献。未来的研究应检验减缓表观遗传学衰老速度的干预措施是否与延长健康和寿命有关。
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