Temporal Dynamics of Epigenetic Aging and Frailty From Midlife to Old Age.

Jonathan K L Mak, Ida K Karlsson, Bowen Tang, Yunzhang Wang, Nancy L Pedersen, Sara Hägg, Juulia Jylhävä, Chandra A Reynolds
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Abstract

Background: DNA methylation-derived epigenetic clocks and frailty are well-established biological age measures capturing different aging processes. However, whether they are dynamically linked to each other across chronological age remains poorly understood.

Methods: This analysis included 1 309 repeated measurements in 524 individuals aged 50-90 years from the Swedish Adoption/Twin Study of Aging. Frailty was measured using a validated 42-item frailty index (FI). Five epigenetic clocks were calculated, including 4 principal component (PC)-based clocks trained on chronological age (PCHorvathAge and PCHannumAge) and aging-related physiological conditions (PCPhenoAge and PCGrimAge), and a pace of aging clock (DunedinPACE). Using dual change score models, we examined the dynamic, bidirectional associations between each of the epigenetic clocks and the FI over age to test for potential causal associations.

Results: The FI exhibited a nonlinear, accelerated increase across the older adulthood, whereas the epigenetic clocks mostly increased linearly with age. For PCHorvathAge, PCHannumAge, PCPhenoAge, and PCGrimAge, their associations with the FI were primarily due to correlated levels at age 50 but with no evidence of a dynamic longitudinal association. In contrast, we observed a unidirectional association between DunedinPACE and the FI, where a higher DunedinPACE predicted a subsequent increase in the FI, but not vice versa.

Conclusions: Our results highlight a temporal order between epigenetic aging and frailty such that changes in DunedinPACE precede changes in the FI. This potentially suggests that the pace of aging clock can be used as an early marker of the overall physiological decline at system level.

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从中年到老年的表观遗传衰老和虚弱的时间动力学。
背景:DNA甲基化衍生的表观遗传时钟和虚弱是公认的生物年龄测量,捕捉不同的衰老过程。然而,人们对它们是否在按时间顺序排列的年龄段内动态地相互联系仍知之甚少。方法:该分析包括瑞典收养/双胞胎老龄化研究中524名50至90岁的个体的1309次重复测量。虚弱是使用经验证的42项虚弱指数(FI)来测量的。计算了五个表观遗传学时钟,包括四个基于主成分(PC)的时钟,这些时钟根据时间年龄(PCHorvathAge、PCHannumAge)和衰老相关的生理条件(PCPhenoAge、PCGrimAge)以及衰老速度时钟(DunedinPACE)进行训练。使用双重变化评分模型,我们检查了每个表观遗传时钟和FI之间随年龄变化的动态双向关联,以测试潜在的因果关联。结果:FI在整个成年期呈非线性加速增长,而表观遗传学时钟大多随年龄呈线性增长。对于PCHorvathAge、PCHannumAge、PCPhenoAge和PCGrimAge,它们与FI的相关性主要是由于50岁时的相关水平,但没有证据表明存在动态纵向相关性。相反,我们观察到DunedinPACE和FI之间存在单向关联,其中较高的DunedinPPACE预测FI随后会增加,但反之亦然。结论:我们的研究结果强调了表观遗传衰老和虚弱之间的时间顺序,因此DunedinPACE的变化先于FI的变化。这可能表明衰老时钟的速度可以作为系统水平整体生理下降的早期标志。
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