Adaptive mechanisms to hematocrit levels of 0.85 in our erythropoietin overexpressing mice (tg6) include increased plasma nitric oxide levels and erythrocyte (RBC) flexibility. Doubled reticulocyte counts in tg6 suggest an increased RBC turnover. Here we show that compared to wild type (wt), RBC lifespan in tg6 is 70% lower. Transgenic mice appear to have a younger RBC population as indicated by higher intercellular water and potassium content, higher flexibility, decreased density, increased surface to volume ratio and decreased osmotic fragility. Interestingly despite seeming to be younger, tg6 RBC population also has markers of increased senescence such as decreased surface CD47 and sialic acids, signs of oxidative stress and increased band 4.1a to 4.1b ratio. In vivo tracking of PKH26- labeled RBCs in tg6 revealed dramatically increased RBC uptake by liver macrophages along with reduced splenic erythro- phagocytosis. Moreover transgenic macrophages showed increased phagocytosis of both tg6 and wt RBCs. Phagocytosis of transgenic RBCs by both tg6 and wt macrophages was higher than that of wt RBC. In conclusion the transgenic RBC population has properties of younger as well as more senescent cells. The latter might increase attractiveness of tg6 RBC for macrophages and therefore, together with an increased number of macrophages, RBC turnover.