Metabolic regulation of human DNA methylation clocks

人类 DNA 甲基化时钟的代谢调控

• 批准号: 10341144
• 负责人: Martin Picard
• 金额: $ 65.03万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341144
• 关键词: Acceleration; Acute; Address; Age; Aging; Algorithms; Animal Model; Behavior; Biological; Biological Aging; Biological Markers; Biology; Biometry; Blood; CDKN2A gene; Cell Aging; Cell division; Cell model; Cells; Chronic; Chronology; Coupled; Cultured Cells; DNA; DNA Methylation; DNA Sequence Alteration; DNA analysis; Data; Data Analyses; Defect; Disease; Elderly; Electron Transport; Epigenetic Process; Etiology; Exhibits; Female; Fibroblasts; Foundations; Gene Expression; Genes; Genetic; Genome; Genomics; Geroscience; Glucocorticoids; Goals; Grant; Human; Human body; IL6 gene; In Vitro; Individual; Individual Differences; Inflammation; Inflammatory; Interleukin-6; Intervention; Length; Life; Life Stress; Link; Location; Longevity; Longitudinal Studies; Maps; Measures; Mediator of activation protein; Meta-Analysis; Metabolic; Metabolic dysfunction; Methods; Mitochondria; Mitochondrial DNA; Modeling; Modification; Molecular Profiling; Monitor; Mutation; Nature; Oxygen; Patients; Pattern; Persons; Pharmacology; Physiological; Process; Psychosocial Stress; Publications; Regulation; Reproducibility; Research; Resolution; Resources; Role; Sex Differences; Signal Transduction; Skin; Stress; System; Testing; Ticks; Time; Twin Multiple Birth; United States National Institutes of Health; Woman; Work; age related; aged; base; biobank; causal model; cohort; cytokine; data modeling; demethylation; experimental study; genetic approach; genomic locus; high dimensionality; human DNA; human tissue; in vivo; insight; male; men; mitochondrial dysfunction; mitochondrial genome; modifiable behavior; mortality; novel; personalized predictions; pre-clinical; prediction algorithm; respiratory; response; stressor; telomere; temporal measurement

There are substantial inter-individual differences in biological aging trajectories, but the origin of these differences is unclear. One specific cellular component that sustains life and fuels stress adaptation are mitochondria, which contain their own genome and generate metabolic intermediates necessary for epigenetic modifications. As a result, genetic defects in mitochondria shorten lifespan in both animal models and patients with mtDNA defects, possibly via the influence of mitochondrial signaling on gene expression and the epigenetic machinery, which includes DNA methylation (DNAm). Reliable changes in DNAm occur with advancing age at specific genomic locations, which have been captured and integrated in predictive algorithms called epigenetic clocks. These clocks predict DNAmAge and have been validated and meta-analyzed in large human cohorts demonstrating that DNAmAge predicts mortality and age-related diseases. But little is known about what clocks actually measure (i.e., what makes them tick), and about their modifiability by metabolic factors across the lifespan. To map the life-long behavior of epigenetic clocks and their responses to both stress mediators and mitochondrial dysfunction, we have developed a primary human fibroblasts cellular lifespan model where: i) DNAm signatures of aging are conserved, ii) the rate of DNAm aging is accelerated about 70 times relative to the human body, iii) metabolic and mitochondrial dysfunction reduces lifespan (i.e., the Hayflick limit) by 25-50%, and iv) other aging biomarkers including ccf-mtDNA and the pro-inflammatory cytokine IL6 are also progressively induced across the cellular lifespan. In Aim 1, we will characterize DNAm aging trajectories across the entire cellular lifespan in both female and male cells using four different global DNAmAge algorithms, a gene-based approach, and by modeling single-CpG trajectories. There results will be validated and extended into available human aging cohorts. In Aim 2, we will examine the modifiability of DNAm clocks with two interventions that reliably decrease the Hayflick limit: i) we will use converging pharmacological and genetic approaches to induce specific mitochondrial respiratory defects, and ii) expose cells to chronic glucocorticoid stimulation to recapitulate the effects of chronic psychosocial stress known to accelerate biological aging in humans. In the final aim, we will perform studies to understand how clock-based DNAmAge relate to other validated aging biomarkers including the expression of age-related genes (Elovl2, p16INK4a), telomere length, circulating cell-free mtDNA (ccf-mtDNA), and the inflammatory cytokine IL-6. Moreover, additional experiments will be performed to establish the contribution of cell division to epigenetic age acceleration, the role of ambient oxygen, and to test the effect of a DNA demethylation agent on other aging biomarkers and on lifespan. Overall, these studies will uncover novel longitudinal associations between epigenetic clocks and human aging biomarkers, and establish the role of mitochondrial signaling as a driver of cellular aging in a human system.

在生物衰老轨迹中存在着大量的个体间差异，但这些差异的起源 差异不清楚。维持生命和刺激压力适应的一种特定细胞成分是 线粒体，其中包含自己的基因组，并产生代谢中间体所必需的表观遗传 修改.因此，线粒体的遗传缺陷缩短了动物模型和患者的寿命 线粒体DNA缺陷，可能是通过线粒体信号对基因表达的影响， 表观遗传机制，包括DNA甲基化（DNAm）。DNA m的可靠变化发生在 在特定的基因组位置上的年龄增长，这些位置已经被捕获并整合到预测算法中 称为表观遗传时钟。这些时钟预测DNA年龄，并已得到大规模验证和荟萃分析 人类队列表明DNAmAge预测死亡率和年龄相关疾病。但鲜为人知的 关于时钟实际测量的内容（即，是什么使它们滴答作响），以及它们通过代谢的可修改性 影响整个生命周期的因素。为了绘制表观遗传时钟的终身行为以及它们对两者的反应， 应激介质和线粒体功能障碍，我们已经开发了一种原代人成纤维细胞 寿命模型，其中：i）老化的DNAm签名被保存，ii）DNAm老化的速率被加速 相对于人体约70倍，iii）代谢和线粒体功能障碍缩短寿命（即， 海弗利克极限）降低25- 50%，和iv）其它老化生物标志物，包括ccf-mtDNA和促炎性细胞因子。 细胞因子IL 6也在整个细胞寿命中被逐渐诱导。在目标1中，我们将表征DNAm 使用四种不同的全球性方法，在女性和男性细胞的整个细胞寿命中， DNAmAge算法，一种基于基因的方法，并通过建模单CpG轨迹。结果会是 验证并扩展到可用的人类老化队列中。在目标2中，我们将检查 DNA时钟与两个干预，可靠地降低海弗利克限制：i）我们将使用收敛 诱导特异性线粒体呼吸缺陷的药理学和遗传学方法，和ii）暴露 细胞对慢性糖皮质激素刺激的反应，以概括已知的慢性心理社会应激的影响， 加速人类的生物衰老。在最后的目标，我们将进行研究，以了解如何时钟为基础的 DNAmAge涉及其他经验证的衰老生物标志物，包括年龄相关基因的表达（Elovl 2， p16 INK 4a）、端粒长度、循环无细胞mtDNA（ccf-mtDNA）和炎性细胞因子IL-6。 此外，将进行额外的实验以确定细胞分裂对表观遗传的贡献。 年龄加速，环境氧气的作用，并测试DNA去甲基化剂对其他 老化生物标志物和寿命。总的来说，这些研究将揭示新的纵向关联， 表观遗传时钟和人类衰老生物标志物，并建立线粒体信号转导作为驱动因素的作用， 人体系统中的细胞衰老