Erythropoietin suppresses D-galactose-induced aging of rats via the PI3K/Akt/Nrf2-ARE pathway

EPO (erythropoietin) is a hormone-like substance with a putative role in hematopoietic regulation. Current research suggests that it exerts a neuroprotective effect by enhancing the activity of antioxidant enzymes. Our previous studies in vitro have confirmed that EPO can delay senescence of cultured neurons by activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and the phosphoinositide-3-kinase (PI3K)/AKT pathway. Thus we set out to further substantiate the mechanism in vivo. A rat model of aging was induced by continuous subcutaneous injection of 5% D-galactose for 6 weeks. Starting at the 7th week, physiological saline or EPO was administered twice daily. LY294002, an inhibitor of the PI3K/AKT pathway, was also given to one of the groups. Improvement of learning and memory abilities were observed in the EPO intervention group. Raised levels of Cu-Zn SOD protein were detected by immunohistochemical staining and Western blot after using EPO, together with increased expression of PI3K/AKT pathway proteins. Concomitantly, there was an increase in expression of Nrf2 mRNA and a decrease in expression of Keap1 mRNA by qRT-PCR. All these effects were not found in the group injected with LY294002. We conclude that EPO can suppress aging by reducing oxidative stress. The proposed mechanism is an upregulation of the PI3K/Akt/Nrf2-ARE pathway and thus maintenance of expression and activation of antioxidant enzymes in aging rats.