Environmental stressors, such as ionizing radiation, accelerate aging by causing DNA damage and triggering pathways that lead to cell cycle arrest, apoptosis, and subsequent inflammation. The thrombopoietin receptor agonist romiplostim (RP), which is used as a clinical treatment for chronic idiopathic thrombocytopenic purpura and aplastic anemia, is known to be promising in reducing radiation-induced tissue damage. In this study, we established a mouse model of radiation-induced premature aging to evaluate the potential of RP in ameliorating this process. Female C57BL/6JJcl mice were subjected to total body irradiation with various irradiation schedules. Mice irradiated with 5 Gy every 4 weeks (total dose of 10 Gy over 2 months) showed a significant aging phenotype, including graying hair and elevated serum aging markers (CDKN2A/p16INK4a, tumor necrosis factor-α (TNF-α), and C-reactive protein), compared with sham-irradiated controls. RP was intraperitoneally administered to the mouse model (10 μg/kg weekly or 50 μg/kg every 4 weeks). Treatment significantly reduced TNF-α levels by 15% and the area of graying body hair by 70%. Although bone marrow cell recovery was incomplete, spleen cell counts were significantly restored (2-fold) by 50 μg/kg RP, and SA-β-gal activity, a marker of cellular senescence, was also significantly suppressed by approximately 15%. These findings suggest that RP may partially ameliorate radiation-induced premature aging, providing a basis for future research addressing health issues associated with aging and radiation exposure.
RP activates the Nrf2‐Keap1 signaling pathway in SPCs, leading to the induction of target genes involved in redox regulation and antioxidant defense. It enhances cellular redox buffering capacity, suppresses the radiation‐induced ROS accumulation, attenuates oxidative DNA damage through nonhomologous end joining repair, and reduces apoptotic cell death. RP also suppresses the radiation‐induced increase in serum plasminogen activator inhibitor (PAI‐1), a key regulator of inflammation and cellular senescence. These results suggest that RP may also ameliorate radiation‐induced premature aging by sequentially suppressing oxidative stress, DNA damage, and senescence‐associated inflammatory signaling via Nrf2‐mediated antioxidant activation. Notably, even at a dose of 10 μg/kg RP, which is within the clinical range, partial suppression of inflammatory markers was observed, consistent with an effect via these mechanisms.