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 早期生命逆境（ELA）与许多最常见疾病的较晚生活风险增加有关 衰老，包括心血管，自身免疫性和神经退行性疾病，以及过早死亡率。 但是，ELA对与年龄相关结局的影响的机理基础仍然很少了解，从而限制了我们的 设计有效的治疗或干预策略的能力。在分子水平上，ELA对以后的生活产生 人们认为生理过程是由基因调节稳定变化介导的。但是，实用 和道德原因，在人类的这一领域工作仅限于少数样本类型（例如唾液， 循环血细胞）。结果，我们对ELA之间的关系缺乏全面的理解 以及与衰老相关疾病有关的许多器官系统和环境中的基因调节。我 将通过研究既定的组织和上下文特异性基因调节的影响来解决这一差距 衰老的灵长类动物模型：自由射程圣地亚哥的猕猴。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个组织中产生 来自100名先前安乐死的成年人。有纵向收集的人口统计和行为数据可用 对于同一个人，这将使我能够与人类密切相关的ELA措施进行编译，并 探索ELA对组织特异性表观基因组和转录组功能的影响（AIM 1）。另外，我会的 在暴露之前和之后，进行新的实验，以测量血细胞中全基因组基因的表达 5个促炎分子（n = 100个个体）；这些数据将使我能够检验ELA具有的假设 当将细胞推到促炎状态时，对免疫基因调节的强烈影响。我会 专注于这种细胞环境，因为慢性炎症是大多数衰老疾病的标志（AIM 2）。 最后，使用AIM 1和2的数据，我将执行后续分析以了解个人间个体变化 对ELA的反应，即性别是否会改变ELA对基因调节变异的影响。结论， 该项目将提供迄今为止的最全面的图片和ELA的环境特定性质 分子水平的影响。它将使用公认的灵长类动物模型来做到这一点，该模型绕过报告 人类ELA研究固有的偏见和混淆，同时仍提供必要的自然主义 了解早期经验的社会生态环境。此外，通过利用灵长类动物模型，我将 能够解决ELA如何嵌入套件的终身分子和生理过程中 在人类中几乎不可能进行大规模采样但与最普遍的疾病有关的组织 衰老（例如大脑，心脏，脂肪）。这项工作将共同提高我们对基因调节的理解 机制的功能使早期生活侮辱成人长期生理记忆。