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，从而影响 生物老化。通过职业暴露、医疗治疗或 涉及电离辐射(IR)的环境灾难，无论是由于核事故、核战争、 和/或恐怖袭击(例如，对核能设施的袭击、脏弹)与 当代公共卫生。然而，这种暴露造成的健康影响很难预测 对不同的剂量率、暴露持续时间、特定年龄的影响以及环境和社会背景 曝光。尽管测试每个组合场景的结果是不可行的，但一个基本的 了解环境和年龄相关变量如何与IR暴露相互作用 通过将环境复杂性和现实的剂量方案结合在一起的方法。 最近的进展表明，表观基因组在生物衰老中发挥了作用，因为它提供了一个分子背景 将遗传和环境影响整合到老龄化计划中。表观遗传时钟总结了 从基因组中选择的一组基因座读出与年龄相关的高甲基化和低甲基化 它们共同能够以高精度预测年龄段。尽管他们史无前例 准确地说，表观遗传时钟指示的年龄可能与个人的实际年龄不同。震级和 这种表观遗传学到时间序列的年龄错配的方向性与生理功能和 疾病风险。例如，相对于他们的实际年龄，较高的表观遗传年龄与 癌症、心脏病和全因死亡。表观遗传学到年代学年龄的根本原因 不和谐没有得到解决，但遗传和环境因素似乎都起到了作用。从经验上讲 解决环境条件和表观遗传老化之间的因果关系，这个项目将采取 新开发的表观遗传时钟对实验和遗传易驯化的青冈鱼的优势 (Oryzias Latipe)模型。 这项工作包括三个主要目标：(1)检验长期暴露于 环境相关剂量的电离辐射加速并塑造表观遗传衰老轨迹。(2) 确定个人的发育暴露史如何与随后的辐射暴露相互作用 影响生物衰老轨迹。(3)确定在以下情况下在整个生命周期内出现的脆弱性窗口 环境暴露对表观遗传衰老轨迹的影响不成比例。共同努力，这项工作将 促进生命历程和毒理学理解环境挑战与 辐射灾难事件塑造了生物老化和伴随而来的生物生理学。

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.