Radiation exposure can accelerate DNA methylation changes linked to aging clocks by causing direct and indirect damage to cellular DNA, which influences epigenetic regulation and cellular aging processes. When cells are exposed to radiation, the DNA suffers damage such as strand breaks and base modifications. This damage triggers cellular stress responses, including activation of DNA repair mechanisms and changes in the epigenetic landscape, notably DNA methylation patterns. These methylation changes are a key component of biological aging clocks, which measure the biological age of cells and tissues based on DNA methylation status.
DNA methylation is a chemical modification where methyl groups are added to cytosine bases in DNA, primarily at CpG sites. This process regulates gene expression and is dynamic throughout life, influenced by both genetic and environmental factors. Aging is characterized by a global decrease in DNA methylation (hypomethylation) alongside localized increases (hypermethylation) at specific gene regions. Radiation exposure can exacerbate these age-related methylation changes by inducing oxidative stress and mitochondrial dysfunction, which further disrupts cellular homeostasis and promotes cellular senescence—a state of irreversible cell cycle arrest associated with aging.
Mitochondrial dysfunction caused by radiation leads to excessive production of reactive oxygen species (ROS), which damage DNA and other cellular components. This oxidative stress activates pathways involving proteins such as p53 and p21, which regulate cell cycle arrest and senescence. Senescent cells accumulate with age and contribute to tissue dysfunction. Radiation-induced mitochondrial iron overload and lipid peroxidation also promote ferroptosis, a form of cell death linked to aging-related tissue decline. These processes collectively accelerate the biological aging of cells, reflected in altered DNA methylation patterns that aging clocks detect.
Moreover, radiation can cause somatic mutations in genes that regulate epigenetic modifiers like DNA methyltransferases (DNMTs) and ten-eleven translocation enzymes (TETs), which control the addition and removal of methyl groups. Mutations or dysregulation in these enzymes can lead to abnormal methylation patterns, further accelerating epigenetic aging. For example, loss-of-function mutations in TET2 and DNMT3A are associated with increased risk of age-related diseases and are more common in older individuals, indicating a link between radiation-induced mutations and accelerated epigenetic aging.
Studies on childhood cancer survivors who received radiation therapy show increased epigenetic age compared to non-exposed individuals, suggesting that radiation exposure in humans can indeed accelerate the biological aging process through epigenetic mechanisms. This acceleration is thought to contribute to the higher incidence of age-related diseases observed in these populations.
In addition to direct DNA damage, radiation influences the tumor microenvironment and cellular metabolism, which can affect DNA repair and epigenetic regulation. Metabolites like fumarate, which support DNA repair, are involved in maintaining genomic stability after radiation exposure, but disruptions in these metabolic pathways can also contribute to aging-related epigenetic changes.
In summary, radiation accelerates DNA methylation changes linked to aging clocks by inducing DNA damage, mitochondrial dysfunction, oxidative stress, and mutations in epigenetic regulators. These effects promote cellular senescence and disrupt normal epigenetic patterns, leading to an accelerated biological aging process detectable by DNA methylation-based aging clocks. This understanding is crucial for assessing long-term health risks of radiation exposure, including in medical treatments and space travel, where radiation levels are elevated.
