Integrating environment-by-epigenome interactions into a tractable model of epigenetic aging

项目摘要 该项目的目标是发现环境如何与表观遗传衰老过程相互作用， 生物老化通过职业照射、医学治疗或 涉及电离辐射（IR）的环境灾害，无论是由于核事故，核战争， 和/或恐怖袭击（例如，对核能设施的攻击，脏弹）与 当代公共卫生。然而，由于这些接触对健康的影响很难预测， 不同的剂量率、接触时间、年龄效应以及环境和社会背景， exposure.虽然测试每个组合场景的结果是不可行的，但一个基本的 可以理解环境和年龄相关变量如何与红外线照射相互作用 通过结合环境复杂性和现实剂量方案的方法。 最近的进展表明表观基因组在生物衰老中的作用，因为它提供了一个分子背景 将遗传和环境影响整合到衰老计划中。表观遗传时钟总结了 从基因组中选择的基因座读出年龄相关的高甲基化和低甲基化， 都能够高精度地预测实际年龄。尽管他们前所未有的 准确性，表观遗传时钟显示的年龄可能与个人的实际年龄不同。的幅度和 这种表观遗传与实足年龄不匹配的方向性与生理功能有关， 疾病风险。例如，相对于他们的实足年龄，晚期表观遗传年龄与以下因素有关： 癌症心脏病和全因死亡率表观遗传至实足年龄的根本原因 不一致性没有得到解决，但遗传和环境因素似乎都发挥了作用。进行实证 该项目将解决环境条件与表观遗传衰老之间的因果关系， 最近开发的实验和遗传上易处理的青鳉鱼表观遗传时钟的优势 （Oryzias latipes）模型。 这项工作包括三个主要目标：（1）测试假设，慢性暴露于 与环境有关的电离辐射剂量加速并形成表观遗传老化轨迹。（二） 确定个体的发育暴露史如何与随后的辐射暴露相互作用， 影响生物老化轨迹。(3)确定整个生命周期中出现的脆弱性窗口， 环境暴露不成比例地影响表观遗传衰老轨迹。这项工作将 推进生命历程和毒理学的理解，如何与环境挑战相关的 放射性灾难事件影响生物老化和随之而来的生物生理学。

Project Summary The goal of the project is to discover how the environment interacts with epigenetic aging processes to affect biological aging. Risk of radiation exposure occurring through occupational exposures, medical therapies, or environmental disasters involving ionizing radiation (IR), either due to nuclear accidents, nuclear warfare, and/or terrorist attacks (e.g., attacks on nuclear energy facilities, dirty bombs) are acutely relevant to contemporary public health. However, health impacts resulting from such exposures are difficult to predict due to variable dose rates, duration of exposure, age-specific effects, and the environmental and social context of exposure. Although testing the outcome of each combinatorial scenario isn’t feasible, a fundamental understanding of how environmental and age-dependent variables interact with IR exposure can be achieved through approaches that incorporate environmental complexity and realistic dosing regimens. Recent advances demonstrate a role for the epigenome in biological aging as it provides a molecular context for integrating both genetic and environmental influences into aging programs. Epigenetic clocks summarize the readout of age associated hyper- and hypo-methylation from a selection of loci across the genome which are collectively capable of predicting chronological age with high accuracy. Despite their unprecedented accuracy, the age indicated by epigenetic clocks can differ from an individual’s actual age. The magnitude and directionality of this epigenetic-to-chronological age mismatch is associated with physiological function and disease risk. For example, advanced epigenetic age relative to their chronological age is associated with cancer, heart disease, and all-cause mortality. The underlying causes of epigenetic-to-chronological age discordance are not resolved but both genetic and environmental factors appear to play a role. To empirically address causal relationships between environmental conditions and epigenetic aging, this project will take advantage of recently developed epigenetic clocks for the experimentally and genetically tractable medaka fish (Oryzias latipes) model. The work encompasses three primary objectives: (1) Test the hypothesis that chronic exposure to environmentally relevant doses of ionizing radiation accelerate and shape epigenetic aging trajectories. (2) Determine how an individual’s developmental exposure history interacts with subsequent radiation exposure to affect biological aging trajectories. (3) Identify windows of vulnerability occurring across the lifespan in which environmental exposures disproportionately impacts epigenetic aging trajectories. Together, this work will advance a life course and toxicological understanding of how environmental challenges associated with radiological disaster events shape biological aging and attendant organismal physiology.