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.

项目摘要 早期生活逆境（ELA）与许多最常见疾病的晚年风险增加有关。 衰老，包括心血管、自身免疫和神经退行性疾病，以及过早死亡。 然而，ELA对年龄相关结果影响的机制基础仍然知之甚少，限制了我们的研究。 设计有效的治疗或干预策略的能力。在分子水平上，ELA对以后的生活有影响 生理过程被认为是由基因调控的稳定变化介导的。但是，对于实际 和伦理原因，在人类中这一领域的工作已被限制在少数样品类型（例如，唾液， 循环血细胞）。因此，我们缺乏对ELA之间关系的全面了解 以及与衰老相关疾病相关的许多器官系统和环境中的基因调控。我 将通过研究ELA对组织和环境特异性基因调控的影响来解决这一差距， 衰老的灵长类动物模型：圣地亚哥岛自由活动的恒河猴。为此，我将利用基因组- 广泛的DNA甲基化和基因表达数据，目前正在收集的15个组织中生成 来自100个之前被安乐死的成年人纵向收集的人口统计和行为数据是可用的 对于相同的个体，这将使我能够编译ELA措施与人类密切相关， 探索ELA对组织特异性表观基因组和转录组功能的影响（目的1）。另外，我将 进行新的实验，以测量暴露前后血细胞中的全基因组基因表达， 5种促炎分子（n=100人）;这些数据将使我能够检验ELA具有 尤其是当细胞被推到促炎状态时，对免疫基因调节的强烈影响。我会 关注这种细胞环境，因为慢性炎症是大多数衰老疾病的标志（目标2）。 最后，使用目标1和2的数据，我将进行随访分析，以了解 对ELA的反应，即性别是否改变ELA对基因调控变异的影响。会议结束时， 该项目将提供迄今为止关于环境影响评估的组织和特定环境性质的最全面的图像 分子水平的影响。它将使用一个完善的灵长类动物模型来做到这一点， 偏见和混淆固有的人类ELA研究，同时仍然提供了必要的，自然的， 社会生态学背景下理解早期的经验。此外，通过利用灵长类动物模型， 能够解决ELA如何嵌入到整个套件的终身分子和生理过程中 这些组织几乎不可能在人类中大规模取样，但与最流行的疾病有关， 老化（例如，脑、心脏、脂肪）。总之，这项工作将促进我们对基因调控机制的理解。 这些机制的功能是将早期生活中的伤害嵌入老年人的长期生理记忆中。