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

成人表观遗传学和端粒长度与改善早期营养有关

• 批准号: 10562425
• 负责人: ARYEH DAVID STEIN
• 金额: $ 67.34万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10562425
• 关键词: 2 year old; 3 year old; Address; Adult; Affect; Age; Age Months; Age Years; Aging; Anthropometry; Biological Aging; Biological Assay; Biological Markers; Body mass index; Central America; Cessation of life; Child; Child Malnutrition; China; Chronology; Collaborations; Conceptions; Country; DNA; DNA Methylation; Data Collection; Development; Diabetes Mellitus; Diet; Dietary Intervention; Disease; Elderly; Enrollment; Environment; Epigenetic Process; Exposure to; Face; Famines; Freezing; Goals; Guatemala; Health; Height; Human; Incidence; Income; Individual; Infant; Intervention; Intervention Trial; Length; Leukocytes; Life; Life Cycle Stages; Life Expectancy; Link; Longevity; Longitudinal Studies; Malnutrition; Measures; Mendelian randomization; Metabolic; Netherlands; Nutrition Indexes; Nutritional Study; Nutritional status; Outcome; Panama; Paper; Participant; Pathway interactions; Pattern; Persons; Physiological; Pregnancy; Pregnant Women; Premature aging syndrome; Prenatal Nutrition; Prevention; Prevention strategy; Productivity; Prospective, cohort study; Proteins; Publishing; Randomized; Recording of previous events; Research; Research Institute; Research Personnel; Resource-limited setting; Risk Factors; Role; Sampling; Site; Strategic Planning; Subgroup; Supplementation; Treatment Protocols; United States National Institutes of Health; Universities; adverse outcome; candidate marker; cohort; design; diabetes risk; early childhood; early-life nutrition; effectiveness evaluation; epigenome-wide association studies; experience; follow-up; healthspan; healthy aging; high body mass index; improved; indexing; innovation; intergenerational; low and middle-income countries; methylation pattern; modifiable risk; multidisciplinary; novel; nutrition; nutritional supplementation; offspring; premature; prevent; public health relevance; stressor; telomere

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.

项目摘要/摘要 我们的广泛目标是通过解决关键研究， 对更有效的缓解努力构成挑战的差距，特别是在中低收入国家 国家我们的中心工作假设是，最佳的早期营养减少生理老化，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， 生命历程基本原理扩展了研究小组先前的关键发现，特别是（1）妊娠期 暴露于荷兰饥荒导致成年期可观察到的表观遗传差异;（2）端粒长度 婴儿和儿童的早期生活母亲的因素和代谢指标不同;（3）暴露于营养 补充干预导致37-52岁糖尿病发病率降低。我们一直在跟踪一个独特的 在儿童时期参加营养补充干预试验的一组个体， 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前1,000天 在怀孕和两岁之间;将对完全暴露的参与者与部分暴露的参与者进行比较 （前1,000天中的0-999天）和无干预暴露。在这项研究中，我们建议从 2015-2017年期间从这些现已成年的队列参与者（n= 1，139）中收集的冷冻血沉棕黄层。我们将 分析样品的DNAm和白细胞端粒长度，这是两个哺乳动物衰老的标志。在目标1中， 我们将评估前1,000天内营养补充对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 与早期营养暴露相关的研究中心，采用孟德尔随机化方法评估因果关系 糖尿病或BMI。在目标2中，我们将确定（1）在最初的1000年中是否需要补充营养， （2）生命过程营养状态轨迹与较长的白细胞端粒长度相关。这 一项创新的研究将是一个机会，以检查有效的可操作的早期生命营养 对人类健康跨度的干预。这将是第一个利用孟德尔遗传学的表观基因组关联研究。 随机化以评估据我们所知的生命早期营养补充和成人代谢结果。如果 成功的，这项研究有可能确定新的亚临床生理衰老指标，营养， 这可能导致更好的干预影响评估和预防战略， 衰老这项创新的多学科研究最适合回答与早期疾病有关的深刻问题。 人类成年期健康寿命的决定因素。它建立在广泛（> 50年）和生产力（>300年）的基础上 发表的论文）与这一队列的经验，以及经验丰富的， 埃默里大学、中美洲和巴拿马研究所以及Vitalant研究所的多产研究人员 院