## 4 Discussion
### Main Discussion
Although possible changes in ROS parameters were not investigated in the present study, due to the above information, it can be speculated here that the impaired hemorheology herein may at least partly be due to increased ROS. According to the CD71\({}^{+/-}\) and TO\({}^{+/-}\) staining, the subtraction of stress reticulocytes significantly increased after HE [16]. During erythropoietin stress, reticulocytes exit early from the hematopoietic tissues, increasing circulating reticulocyte numbers. Although this staining approach could not distinguish the relative amounts of very old erythrocytes, the levels of CD47 and CD147 showed a significant aging process in the HE. In contrast, the NE increased the relative proportion of mature erythrocytes significantly and concomitantly suppressed senescence. This has been speculated as a relatively positive effect on accelerating erythrocyte maturation due to lower ROS production within 6 weeks of NE [38]. One of the main factors in erythrocyte aggregation is the surface charge; we speculate that the change in membrane sialic acid with erythrocyte aging or even maturation is mainly responsible for training adaptations [39]. Therefore, both NE and HE partly facilitated aggregation via the intrinsic factor. In this work, the aggregation of erythrocytes in the dextran solution reflects intrinsic erythrocyte aggregability [40]. Donor illness or old erythrocytes reduce the surface charge density of erythrocytes, thus increasing aggregation in standard dextran solution [41]. Certainly, there are other age-related cellular factors that influence aggregation, since differences between younger and older cells still exist after removing sialic acid from the erythrocyte surface. We demonstrated that, in the presence of fixed fibrinogen concentrations, only HE erythrocytes tended to increase in fibrinogen binding probability and force, whereas NE diminished this response. Conversely, some studies have indicated that the fibrinogen binding probability is decreased upon erythrocyte aging due to progressive impairment of the specific fibrinogen-erythrocyte receptor interaction [5]. In addition to the enhanced presence of PS exposure on erythrocytes with aging following the HE, the increased percentage of reticulocytes may also be a contributor to the increased fibrinogen affinity [42]. The reduced binding probability after the NE was probably related to the glycoprotein receptors IIb/IIIa (GPIb/IIIa). Moderate exercise (60% VO2 max for 40 min) had a positive influence on GPIb/IIIa receptor expression, decreasing its baseline percentage values [43]. The beneficial or detrimental effects of intermittent hypoxia may vary substantially with the concentration of oxygen in the air and the subsequent change in the circulatory redox status under an exercise regimen. Although both 12% oxygen and 15% oxygen for 8 weeks improved the aerobic fitness of subjects by enhancing pulmonary ventilation and tissue oxygen utilization, our team demonstrated that 12% oxygen but not 15% oxygen acute exercise simultaneously enhanced oxidative-stress-induced lymphocyte apoptosis by diminishing cellular antioxidant levels [34]. Therefore, in the present study, the oxygen concentration of the HET was set to 12%. Moreover, chronic intermittent exposure to 12% oxygen for 1 h/day for 8 weeks increased levels of proinflammatory cytokines IL-6 and IL-10 and reduced antioxidative capacity [17]. In contrast to the 12% oxygen, the 15% oxygen moderate hypoxic exercise training increases resistance to disturbance of cardiac hemodynamics by severe hypoxia [11] and further depresses oxidative stress and proinflammatory cytokine production [33]. Taken together, our numerous previous experimental findings helped us to determine effective hypoxic exercise regimens under 15% oxygen instead of 12% to increase aerobic capacity and minimize the risk of inflammatory and thrombotic disorders associated with exercise.