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.

项目概要 早年逆境（ELA）与晚年生活中许多最常见疾病的风险增加有关。 衰老，包括心血管疾病、自身免疫性疾病和神经退行性疾病，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，这限制了我们的研究 设计有效治疗或干预策略的能力。在分子水平上，ELA对晚年生活的影响 生理过程被认为是由基因调控的稳定变化介导的。然而，为了实用 出于道德原因，人类这一领域的工作仅限于少数样本类型（例如唾液、 循环血细胞）。因此，我们对ELA之间的关系缺乏全面的了解。 以及与衰老相关疾病有关的许多器官系统和背景的基因调控。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 灵长类衰老模型：圣地亚哥岛自由放养的恒河猴。为此，我将利用基因组- 目前正在收集 15 个组织中生成广泛的 DNA 甲基化和基因表达数据 来自 100 名之前被安乐死的成年人。提供纵向收集的人口统计和行为数据 对于同一个人，这将使我能够编制与人类密切相关的 ELA 测量值，并 探索 ELA 对组织特异性表观基因组和转录组功能的影响（目标 1）。另外，我将 进行新的实验来测量暴露之前和之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 的假设 当细胞处于促炎状态时，对免疫基因调节的影响尤其强烈。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，我将进行后续分析，以了解个体间的差异 对 ELA 的反应，即性别是否会改变 ELA 对基因调控变异的影响。结论是， 该项目将提供迄今为止关于 ELA 的组织和具体情况的最全面的描述 分子水平的影响。它将使用成熟的灵长类动物模型来做到这一点，从而规避报告 人类 ELA 研究固有的偏见和混淆，同时仍然提供必要的、自然主义的 理解早期经历的社会生态背景。此外，通过利用灵长类动物模型，我将 能够解决 ELA 如何嵌入整个套件的终生分子和生理过程 几乎不可能在人体中大规模取样但与最流行的疾病相关的组织 衰老（例如大脑、心脏、脂肪）。总之，这项工作将增进我们对基因调控如何进行的理解 机制的作用是将早期生活中的侮辱嵌入老年人的长期生理记忆中。