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)与许多最常见的疾病的晚年风险增加有关 老龄化，包括心血管疾病、自身免疫疾病和神经退行性疾病，以及过早死亡。 然而，ELA对年龄相关结果的影响的机制基础仍然知之甚少，限制了我们的 有能力设计有效的治疗或干预策略。在分子水平上，ELA对以后的生命有影响 生理过程被认为是由基因调控的稳定变化所调节的。然而，从实际出发， 由于伦理原因，人类在这一领域的工作仅限于少数几种样本类型(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 以及涉及衰老相关疾病的许多器官系统和背景的基因调控。我 将通过研究ELA对组织和上下文特定基因调控的影响来解决这一差距 衰老的灵长类模型：圣地亚哥卡约的自由放养猕猴。为此，我将利用基因组- 目前正在收集的15个组织的广泛DNA甲基化和基因表达数据 从100名之前被安乐死的成年人。可获得纵向收集的人口统计和行为数据 对于相同的个体，这将使我能够汇编与人类密切相关的ELA测量结果，并 探索ELA对组织特异性表观基因组和转录功能的影响(目标1)。另外，我会 进行新的实验，以测量接触铅前后血细胞全基因组基因的表达 5个促炎分子(n=100个人)；这些数据将使我能够检验ELA具有 当细胞被推到促炎状态时，对免疫基因调节的影响尤其强烈。这就做 关注这一细胞背景，因为慢性炎症是大多数老年病的标志(目标2)。 最后，使用目标1和目标2的数据，我将进行后续分析，以了解在 对ELA的反应，即性别是否改变了ELA对基因调控变异的影响。在其结束时， 该项目将提供迄今为止最全面的ELA组织和特定于上下文的性质的图景 在分子水平上的影响。它将使用一个完善的灵长类模型来实现这一点，该模型绕过了报告 对人类ELA研究固有的偏见和混淆，同时仍提供必要的、自然主义的 理解早期经验的社会生态学背景。此外，通过利用灵长类模型，我将 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 几乎不可能在人类身上大规模取样，但与最流行的疾病有关的组织 衰老(例如，大脑、心脏、脂肪)。总之，这项工作将促进我们对基因调控如何 在老年人的长期生理记忆中嵌入早期生活侮辱的机制起着作用。