Early life effects on later life health and aging: molecular mechanisms and context-dependency

早期生活对晚年健康和衰老的影响：分子机制和背景依赖性

• 批准号: 10665792
• 负责人: Amanda Lea
• 金额: $ 31.7万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665792
• 关键词: Address; Adipose tissue; Adult; Adverse event; Age; Aging; Animal Model; Animals; Area; Autoimmune Diseases; Behavioral; Blood Cells; Brain; Cardiovascular Diseases; Cell division; Cells; Chronic; Chronic Disease; DNA Methylation; Data; Dependence; Development; Diabetes Mellitus; Disease; Early identification; Elderly; Environment; Epigenetic Process; Ethics; Euthanasia; Exhibits; Exposure to; Famines; Female; Funding; Gene Expression; Gene Expression Regulation; Genes; Health; Heart; Human; Immune; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Interferon Type II; Interleukin-1 beta; Intervention; Life; Life Experience; Link; Literature; Macaca mulatta; Measures; Mediating; Memory; Methylation; Modeling; Molecular; Nature; Neurodegenerative Disorders; Obesity; Outcome; Pattern; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Physically Challenged; Physiological; Physiological Processes; Physiology; Population; Predisposition; Premature Mortality; Primates; Regulator Genes; Reporting; Risk; Saliva; Same-sex; Sampling; Siblings; Social Behavior; Social status; Source; TNF gene; Testing; Time; Tissues; Variant; Work; age related; bisulfite sequencing; body system; cell type; design; disorder risk; early experience; early life adversity; epigenomics; experience; experimental study; falls; follow-up; genome-wide; human model; improved; insight; inter-individual variation; kidney dysfunction; mRNA sequencing; male; molecular shape; nonhuman primate; prenatal exposure; response; sex; social; therapeutically effective; trait; transcriptomics

Project Summary Early life adversity (ELA) is associated with an increased later life risk of many of the most common diseases of aging, including cardiovascular, autoimmune, and neurodegenerative diseases, as well as premature mortality. However, the mechanistic basis of ELA effects on age-related outcomes remains poorly understood, limiting our ability to design effective therapeutic or intervention strategies. At the molecular level, ELA effects on later life physiological processes are thought to be mediated by stable changes in gene regulation. However, for practical and ethical reasons, work in this area in humans has been restricted to a handful of sample types (e.g., saliva, circulating blood cells). As a result, we lack a comprehensive understanding of the relationship between ELA and gene regulation across the many organ systems and contexts that are involved in aging-related diseases. I will address this gap by studying ELA effects on tissue- and context-specific gene regulation in an established primate model of aging: the free ranging rhesus macaques of Cayo Santiago. To do so, I will leverage genome- wide DNA methylation and gene expression data that are currently being generated across 15 tissues collected from 100 previously euthanized adults. Longitudinally collected demographic and behavioral data are available for the same individuals, which will allow me to compile ELA measures with close correlates in humans, and to explore the impact of ELA on tissue-specific epigenomic and transcriptomic function (Aim 1). Additionally, I will perform new experiments to measure genome-wide gene expression in blood cells before and after exposure to 5 proinflammatory molecules (n=100 individuals); these data will allow me to test the hypothesis that ELA has especially strong effects on immune gene regulation when cells are pushed to a proinflammatory state. I will focus on this cellular context because chronic inflammation is a hallmark of most diseases of aging (Aim 2). Finally, using data from Aims 1 and 2, I will perform follow up analyses to understand inter-individual variation in the response to ELA, namely whether sex modifies ELA effects on gene regulatory variation. At its conclusion, this project will provide the most comprehensive picture to date of the tissue and context-specific nature of ELA effects at the molecular level. It will do so using a well-established primate model, which circumvents reporting biases and confounds inherent to human ELA studies while still providing a necessary, naturalistic socioecological context for understanding early experiences. Further, by leveraging a primate model, I will be able to address how ELA becomes embedded into lifelong molecular and physiological processes across a suite of tissues that are near impossible to sample at scale in humans but are relevant to the most prevalent disease of aging (e.g., brain, heart, adipose). Together, this work will advance our understanding of how gene regulatory mechanisms function to embed early life insults into long-term physiological memory in aging adults.

项目总结