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/总结