Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
EBioMedicine. 2024 Nov;109:105425. doi: 10.1016/j.ebiom.2024.105425. Epub 2024 Oct 29.
DNA methylation (DNAm), an epigenetic mechanism that regulates gene activity in response to genetic and environmental influences, changes as we age. DNAm at specific sites on the genome can be used to calculate 'epigenetic clocks', which are powerful biomarkers of age, as well as of ageing. However, little is known about how these clock sites 'behave' during development and what factors influence their variability in early life. This knowledge could be used to optimise healthy ageing well before the onset of age-related conditions.
We leveraged results from two longitudinal population-based cohorts (N = 5019 samples from 2348 individuals) to characterise trajectories of adult clock sites from birth to early adulthood. To explore what factors may drive early individual differences at these clock sites, we also tested for enrichment of genetic factors and prenatal exposures based on existing epigenome-wide association meta-analyses.
We find that clock sites (i) diverge widely in their developmental trajectories, often showing non-linear change over time; (ii) are substantially more likely than non-clock sites to vary between individuals already from birth, differences that are predictive of DNAm variation at later ages; and (iii) show enrichment for genetic influences and prenatal environmental exposures, including prenatal smoking, diet and maternal physical health conditions.
These results suggests that age(ing)-related epigenetic processes might originate-and differ between individuals-already very early in development. Understanding what drives these differences may in future help us to devise better strategies to promote healthy ageing.
This research was conducted while C.A.M.C. was a Hevolution/AFAR New Investigator Awardee in Aging Biology and Geroscience Research. Full personal funding details, as well as cohort funding details, can be found in the Acknowledgements.
DNA 甲基化（DNAm）是一种表观遗传机制，它可以根据遗传和环境的影响调节基因活性的变化。随着我们年龄的增长，这种机制会发生变化。基因组特定位置的 DNAm 可以用来计算“表观遗传时钟”，这些时钟是年龄以及衰老的强有力生物标志物。然而，我们对于这些时钟位点在发育过程中如何“表现”以及哪些因素会影响它们在生命早期的可变性知之甚少。这些知识可以用于在与年龄相关的疾病出现之前，优化健康的衰老。
我们利用来自两个纵向人群队列（来自 2348 个人的 5019 个样本）的结果，描述从出生到成年早期的成人时钟位点的轨迹。为了探索哪些因素可能会驱动这些时钟位点的早期个体差异，我们还根据现有的全基因组关联荟萃分析测试了遗传因素和产前暴露的富集情况。
我们发现时钟位点（i）在其发育轨迹中差异很大，通常随着时间的推移表现出非线性变化；（ii）在个体之间从出生开始就存在显著的差异，这些差异可预测以后年龄的 DNAm 变化；（iii）表现出遗传影响和产前环境暴露的富集，包括产前吸烟、饮食和母亲身体健康状况。
这些结果表明，与年龄相关的表观遗传过程可能在发育早期就已经开始，并在个体之间存在差异。了解这些差异的驱动因素可能有助于我们在未来制定更好的策略来促进健康的衰老。
这项研究是在 C.A.M.C. 担任 Hevolution/AFAR 新研究员奖在衰老生物学和老年科学研究期间进行的。完整的个人资助细节以及队列资助细节可以在致谢中找到。
