Free radical theory of erythrocyte aging.

Mature, circulating mammalian erythrocytes have a finite lifespan. The molecular mechanism that determines removal of cells from the circulation remains unknown, but probably involves recognition of senescence antigens by phagocytes, either directly or via an antibody/complement-mediated pathway. It has been proposed that the major senescence antigen in aged erythrocytes is derived from the band 3 protein, the main transmembrane glycoprotein in erythrocytes. Other possible mechanisms for red cell aging include mechanical fatigue, ATP depletion, calcium accumulation, and the generation of reactive oxygen species (ROS). ROS, which damage proteins and initiate lipid peroxidation, can be generated either inside erythrocytes through the hemoglobin oxidation pathway or outside (eg, by stimulated macrophages). The ROS theory of red cell aging has been widely accepted, yet it lacks direct supporting evidence. To test this hypothesis, two critical techniques have been established in this laboratory. First, we determine the lifespan of erythrocytes in vivo using a fluorescent cell labeling technique. Second, transgenic mice have been produced which express high levels of the human antioxidant enzymes, superoxide dismutase and glucose-6-phosphate dehydrogenase, in their erythrocytes. These two techniques will be very useful for the evaluation of the free radical theory of red cell aging.