(A) Wild-type red blood cell development, in which Foxo3 induces the expression of antioxidants such as catalase, GADD45, and MnSOD in the erythroid progenitor. The terminally differentiated erythrocyte then develops normally and survives as expected (a mean of approximately 120 days). (B) As reported by Marinkovic et al. (10) in this issue of the JCI, the lack of Foxo3 in erythroid progenitor cells of Foxo3-null mice results in an increase in ROS in the terminal red blood cell, which ultimately results in a reduction in red blood cell lifespan. These animals also had evidence of hemolytic anemia, including reticulocytosis and splenomegaly. This scenario is similar to that found in G6PD deficiency, in which lack of the enzyme that helps to convert NADP to NADPH results in hemolytic anemia and a shortened red blood cell lifespan. (C) Reversal of this detrimental effect on red blood cell lifespan by administration of exogenous antioxidant to the Foxo3-null animals, most likely due to the decrease in ROS.