Epigenetic responses to social and environmental cues in early life and over the life course: impact on healthy ageing in UK population-based cohorts

表观遗传机制如DNA甲基化是基因功能的关键调节因子。表观遗传信号是可塑的，可以随着内部和外部刺激而改变。因此，表观基因组提供了基因组与环境之间相互作用的机制，我们假设生命早期的刺激和生命过程中的暴露会留下表观遗传标记。（MRC全国健康和发展调查（NSHD）或1946年出生队列，全国儿童发展研究（NCDS）或1958年出生队列，1970年英国队列研究（BCS70）和TwinsUK队列（TwinsUK）），以确定早期生活经验和在生命过程中暴露于社会，环境和生物刺激的表观遗传特征，将发现与衰老期间身体和认知功能的变化联系起来。每项研究都收集了一系列早期生活经验，纵向健康指标和成年生活方式问卷数据，在单个或多个时间点收集的DNA样本，以及在样本子集中，用于后续分析的多个基因组数据。主要研究设计是对来自四个队列的2，336份血液和1，688份口腔样本的纵向数据进行前瞻性分析。这项研究的第一个目的是确定生命早期和整个生命过程中的生物、环境和社会刺激是否会导致成年人DNA甲基化谱的可检测差异。我们将考虑是否有表观遗传协会与一些因素，包括生物，环境和社会因素在子宫内和幼儿期（如出生体重，儿童生长，母亲在怀孕期间吸烟，营养，父母的社会经济地位），并在以后的生活：（如吸烟，饮酒，体育活动，饮食，压力事件，成年社会经济地位）。第二个目的是评估队列之间是否存在DNA甲基化模式的差异，比较包含不同年份（1946年，1958年和1970年）出生的个体的样本，考虑年龄，因为这些可能反映了早期生活中环境和社会影响的队列之间的差异。我们的第三个目标是探索表观遗传学的作用，在健康的功能老化，通过应用一个双重的方法。首先，我们将比较表观遗传特征与跨队列、跨细胞类型（血液和口腔）以及跨不同年龄类别的整个生命过程中的纵向功能健康轨迹。我们将探讨早期生活经历的DNA甲基化特征是否可以介导功能性衰老轨迹（如心血管、肺和认知功能），以及它们是否可以在晚年的社会和环境暴露中逆转。我们的第四个目标是应用一种新的方法来估计生物年龄，即表观遗传时钟，以评估表观遗传衰老的速度，并将其与早期生活刺激以及纵向生物医学、社会和环境轨迹联系起来。子样本的其他分析将包括多个时间点的DNA甲基化谱分析，以估计DNA甲基化的可逆性，血液、口腔和其他组织的跨组织比较，以及用于功能解释的基因表达分析。将在来自四个独立的英国人群队列的3，970个样本中进行复制。研究结果将通过将四个队列中每个队列的适度参与者样本组合成一个大样本来确定早期生命因素对整个生命过程中表观遗传特征的影响，从而建立我们方法的可行性。概念验证方法将允许这种分析扩展到队列内的更大样本，为进一步的资助申请奠定基础，并在英国人口队列中建立表观遗传研究网络。

Epigenetic mechanisms such as DNA methylation are key regulators of gene function. Epigenetic signals are malleable and can change in response to internal and external stimuli. The epigenome thereby provides a mechanism of interaction between the genome with the environment, and we hypothesize that early life stimuli and exposures over the life course leave an epigenetic mark.The proposal will explore DNA methylation in 4,024 samples from four British cohort studies (the MRC National Survey for Health and Development (NSHD) or 1946 birth cohort, the National Child Development Study (NCDS) or 1958 birth cohort, the 1970 British Cohort Study (BCS70), and the TwinsUK cohort (TwinsUK)) in order to identify epigenetic signatures of early life experience and exposure to social, environmental, and biological stimuli over the life course, linking findings to changes in physical and cognitive function during ageing. Each study captures a range of early life experiences, longitudinal health measures and lifestyle questionnaire data from adult life, DNA samples collected at single or multiple time-points, and in a sample subset, multiple genomic data for follow-up analyses. The primary research design is a prospective analysis of longitudinal data across 2,336 blood and 1,688 buccal samples from the four cohorts. The first aim of the research will be to establish whether biological, environmental, and social stimuli in early life and over the life course result in detectable differences in DNA methylation profiles in adults. We will consider whether there are epigenetic associations with a number of factors including biological, environmental and social factors in utero and in early childhood (e.g. birthweight, childhood growth, maternal smoking during pregnancy, nutrition, parental socioeconomic position), and in later life: (e.g. smoking, alcohol consumption, physical activity, diet, stressful events, adult socioeconomic position). The second aim is to assess whether there are differences between cohorts in DNA methylation patterns, comparing samples containing individuals born in different years (1946, 1958 and 1970), accounting for age, since these may reflect differences between cohorts in environmental and social influences in early life. Our third aim is to explore the role of epigenetics in healthy functional ageing by applying a two-fold approach. First, we will compare epigenetic signatures to longitudinal functional health trajectories throughout life across cohorts, across cell types (blood and buccal), and across different age categories. We will explore whether DNA methylation signatures of early life experiences can mediate functional ageing trajectories (such as cardiovascular, lung and cognitive function), and whether they can be reversed in response to social and environmental exposures in later life. Our fourth aim is to apply a new approach to estimate biological age, the epigenetic clock, to assess the rate of epigenetic ageing and relate it to early life stimuli and longitudinal biomedical, social, and environmental trajectories. Additional analyses in subsamples will include DNA methylation profiling at multiple time-points to estimate reversibility of DNA methylation, cross-tissue comparison across blood, buccal, and additional tissues, and gene expression analysis for functional interpretation. Replication will be pursued in 3,970 samples from four independent UK-population-based cohorts.The findings will establish the feasibility of our approach by combining modest samples of participants across each of the four cohorts into a large sample well powered to determine the influence of early life factors on epigenetic signatures throughout the life course. The proof of concept approach will allow such analyses to be extended to larger samples within cohorts by forming the basis for further funding applications and establishing an epigenetic research network across UK population-based cohorts.