Early life influences on Epigenetic Aging in Mexican-American children

项目摘要 表观遗传时钟是高度精确的基于DNA甲基化的生物衰老的生物标志物。脱氧核糖核酸 甲基化时钟可以预测年龄，最近已经成为最准确的分子 生物年龄的标记，与端粒长度、转录和基于蛋白质组的估计器进行比较。 表观遗传年龄估计和年代年龄之间的差异，称为表观遗传年龄加速，是 在生物学上相关，并与所有原因的死亡率、发病率和长寿有关。确实有 几种表观遗传学时钟，它们使用特定组织中已知随年龄而不同的不同CpG位点集(大多数 通常是血液，但有些适用于多种组织类型)与数学算法相结合来计算 表观遗传或DNA甲基化年龄的综合量度。这些发现表明，表观遗传年龄是 对衰老和与年龄相关的疾病，如癌症和肥胖症的有用预测标记。 鉴于表观遗传时钟及其在衰老中的作用是一个相对年轻的研究领域，许多数据缺口 留下来。一些研究表明，环境和社会因素可能会影响表观遗传的时钟滴答率， 可能会影响衰老和发育过程，但数据在某种程度上仍然有限。此外，几乎没有人 已经在儿童中进行了研究，虽然有提示性证据表明，母亲的代谢和 社会人口学因素可能影响DNA甲基化年龄，结果并不一致 学习。此外，新的表观遗传学时钟结合了额外的临床参数并提高了灵敏度 准确性是最近开发出来的，但还没有在儿童身上进行测试。 此前，我们评估了儿童的DNA甲基化情况，随后由健康中心进行了评估 对Salinas母亲和孩子的评估(CHAMACOS)研究，一项农场工人的纵向出生队列 家人。我们发现血液中区域和特定部位的DNA甲基化与性别、年龄显著相关 以及暴露在环境中。在这项提案中，我们将利用现有的DNA甲基化数据来检查 CHAMACOS儿童早期生活因素与表观遗传年龄加速的关系。我们会计算出 CHAMACOS儿童在三个阶段采集的血液中四种不同的表观遗传学时钟估计 儿童期(出生、儿童期中期--9岁，青春期--14岁)。我们将评估它们与时间顺序的相关性 年龄和测定表观遗传年龄加速率。我们将研究表观遗传年龄的关联。 孕期母体因素加速，如代谢参数、产次、年龄和SES因素 和孩子的出生结果(胎龄和出生体重)和性别，以确定影响早期生活的因素 表观遗传年龄加速。这项研究的结果将作为R01提案扩展的基础 我们对CHAMACOS儿童表观遗传衰老分子机制的研究。了解因素 这可能会加速或减缓滴答速度，可能会加强我们对分子机制的理解。 参与与年龄相关的疾病，并帮助确定早期预防目标。

Project Summary Epigenetic clocks are highly accurate DNA methylation-based biomarkers of biological aging. DNA methylation clocks predict chronological age and have recently emerged as the most accurate molecular marker of biological age in comparison to telomere length, transcriptomic, and proteomic based estimators. Differences between epigenetic age estimates and chronological age, called epigenetic age acceleration, are biologically relevant and have been associated with all-cause mortality, morbidity and longevity. There are several epigenetic clocks which use different sets of CpG sites known to differ by age in a specific tissue (most often blood, but some apply to multiple tissue types) in combination with mathematical algorithms to compute an aggregate measure of epigenetic or DNA methylation age. These findings suggest that epigenetic age is a useful predictive marker of aging and age-associated conditions like cancer and obesity. Given that epigenetic clocks and their role in aging is a relatively young field of research, many data gaps remain. Some studies suggest that environmental and social factors may affect epigenetic clock ticking rates, potentially affecting aging and developmental processes yet data remain somewhat limited. Furthermore, few studies have been conducted in children, and while there is suggestive evidence that maternal metabolic and sociodemographic factors may influence DNA methylation age, findings have not been consistent between studies. Also, newer epigenetic clocks incorporating additional clinical parameters and improving on sensitivity and accuracy have recently been developed but not tested in children. Previously, we assessed DNA methylation profiles in children followed by the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study, a longitudinal birth cohort of farmworker families. We found significant associations of regional and site-specific DNA methylation in blood with sex, age and environmental exposures. In this proposal, we will leverage our existing DNA methylation data to examine associations of early life factors with epigenetic age acceleration in CHAMACOS children. We will calculate four different epigenetic clock estimates in blood collected from CHAMACOS children at three stages of childhood (birth, mid-childhood - 9y, and adolescence -14y). We will assess their correlation with chronological age and determine rates of epigenetic age acceleration. We will examine associations of epigenetic age acceleration with maternal factors during pregnancy like metabolic parameters, parity, age, and SES factors and child birth outcomes (gestational age and birthweight) and sex to identify early life factors that influence epigenetic age acceleration. Findings from this study will be used as the basis for an R01 proposal expanding our research on molecular mechanisms of epigenetic aging in CHAMACOS children. Understanding factors that might accelerate or slow ticking rates may strengthen our understanding of the molecular mechanisms involved in age-related conditions and help to identify early targets for prevention.