Low-Dose Caffeine Exposure Protects the Human Genome from Ionizing Radiation-Induced Damage and Prolongs Mouse Longevity

Coffee is one of the most widely consumed beverages in the world and is a rich source of caffeine, a methylxanthine. Here we show that exposure to caffeine significantly reduces ionizing radiation (IR) induced DNA breaks and resulted in no or minimal G2/M arrest within the human cell, in contrast to IR alone. At the molecular level, we demonstrate that when naked plasmid DNA or oligomeric DNA was irradiated, the number of breaks was significantly less in the presence of caffeine. The observed radioprotection was irrespective of its sequence and was due to quenching of ROS by caffeine. Besides, caffeine treatment in NOS2 knockout (KO) mice exhibited a significantly enhanced survival compared to the corresponding WT mice post-irradiation. The transcriptome analysis revealed the upregulation of the key antioxidant genes (Gpx3, Gpx7, Gpx4, Idh1, etc.) involved in playing a role in ROS homeostasis in caffeine-treated mice following exposure to IR, which was further upregulated in the NOS2 KO mice. The increase in lifespan after whole-body irradiation in mice pretreated with caffeine demonstrates the potential of caffeine-mediated radioprotection and provides compelling evidence that caffeine mitigates the detrimental effects of ionizing radiation by reducing ROS and RNS levels and enhancing the expression of antioxidant genes.