Adult epigenetics and telomere length in relation to improved nutrition in early life

项目摘要/摘要 我们的广泛目标是通过解决关键研究来减少过早衰老所造成的后果 差距是对更有效的缓解努力的挑战，特别是在低收入和中等收入 国家。我们的中心工作假设是，最佳的早期营养可以减少生理衰老，特别是 通过对人类DNA相关机制(DNA甲基化[dNaM]、端粒长度)的持续影响 生命历程。这一理论基础延续了研究团队之前的主要发现，特别是(1)妊娠 暴露在荷兰饥荒中导致了成年期明显的表观遗传学差异；(2)端粒长度 婴儿和儿童在早期母体因素和代谢指标上有所不同；以及(3)接触营养 补充干预降低了37-52岁年龄段的糖尿病发病率。我们一直在跟踪一项独特的 儿童时期参加营养补充剂干预试验的人群 1969年至1977年在危地马拉的四个村庄。我们将完全干预暴露定义为生命的头1,000天 在怀孕到两岁之间；完全暴露的参与者将与部分暴露的参与者进行比较 (前1,000天中的0-999天)，没有干预暴露。在这项研究中，我们建议从 2015-2017年间从这些现已成年的队列参与者(n=1139)收集的冷冻黄褐色外套。我们会 检测样本的dNaM和白细胞端粒长度，这是哺乳动物衰老的两个标志。在目标1中， 我们将评估前1,000天的营养补充对dNaM模式和dNaM- 计算表观遗传年龄，包括表观年龄和其他表观遗传时钟。我们还将进一步研究CpG 用孟德尔随机化方法评估因果关系与早期营养暴露相关的部位 患有糖尿病或BMI。在目标2中，我们将确定(1)在前1,000人期间是否进行营养补充 (2)生命过程的营养状况轨迹与较长的白细胞端粒长度有关。这 创新研究将是检验可操作的早期营养的有效性的机会。 对人类健康跨度的干预。这将是第一次利用孟德尔的表观基因组关联研究 据我们所知，随机评估早期营养补充剂和成人代谢结果。如果 这项研究的成功，有可能确定新的亚临床生理性衰老指标，这些指标是营养- 敏感性，这可能导致更好的干预影响评估和早产儿预防战略 衰老。这项创新的多学科研究最适合回答与早期- 人类健康的生命决定因素跨越了成年期。它建立在广泛(&gt；50y)和多产(&gt；300)的基础上 发表的论文)与这一群体的经验，以及有经验的和 埃默里大学、中美洲和巴拿马研究所以及Vitalant Research的富有成效的研究人员 研究所。

Project Abstract / Summary Our broad goal is to reduce the consequences caused by premature aging through addressing key research gaps that represent challenges to more effective mitigation efforts, particularly in low- and middle-income countries. Our central working hypothesis is that optimal early-life nutrition reduces physiologic aging, specifically via persistent impacts on DNA-related mechanisms (DNA methylation [DNAm], telomere length) over the human life course. The rationale extends key previous findings from the study team, particularly that (1) gestational exposure to the Dutch famine resulted in observable epigenetic differences in adulthood; (2) telomere length of infants and children differ by early-life maternal factors and metabolic indicators; and (3) exposure to a nutrition supplementation intervention led to reduced diabetes incidence at age 37-52 y. We have been following a unique cohort of individuals who participated as children in a nutrition supplementation intervention trial conducted in four villages in Guatemala from 1969 to 1977. We define full intervention exposure as the first 1,000 days of life between conception and two years of age; participants with full exposure will be compared to those with partial (0-999 of these ‘first 1,000 days’) and no intervention exposure. In this study, we propose to extract DNA from frozen buffy coats collected between 2015-2017 from these now-adult cohort participants (n=1,139). We will assay samples for DNAm and leukocyte telomere length, which are two mammalian aging hallmarks. In Aim 1, we will evaluate the impact of nutrition supplementation during the first 1,000 days on DNAm patterns and DNAm- calculated epigenetic age, including PhenoAge and other epigenetic clocks. We will also further examine CpG sites associated with early-life nutrition exposure with Mendelian randomization to assess causal associations with diabetes or BMI. In Aim 2, we will determine whether (1) nutrition supplementation during the first 1,000 days, and (2) life course nutritional status trajectories are associated with longer leukocyte telomere length. This innovative study will be an opportunity to examine the effectiveness of an actionable early-life nutrition intervention on the human health span. It will be the first epigenome-wide association study utilizing Mendelian randomization to assess early-life nutrition supplementation and adult metabolic outcomes to our knowledge. If successful, this study has the potential to identify novel subclinical physiologic aging indices that are nutrition- sensitive, which could lead to better intervention impact assessment and prevention strategies for premature aging. This innovative, multidisciplinary study is optimally suited to answer profound questions relating to early- life determinants of the human health span in adulthood. It builds upon extensive (>50y) and productive (>300 published papers) experience with this cohort, and a successful history of collaboration among experienced and productive researchers at Emory University, the Institute of Central America and Panama, and Vitalant Research Institute.