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

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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.