Drosophila to bacteriophage to erythrocyte: the erythrocyte as a model for molecular and membrane aging of terminally differentiated cells.

Senescent cell antigen appears on old cells and marks them for death by initiating the binding of IgG autoantibody and subsequent removal by phagocytes in mammals and other vertebrates. Although the initial studies are done using erythrocytes as a model, senescent cell antigen has been found on all cells examined. Oxidation generates senescent cell antigen in situ. Senescent cell antigen is generated by the modification of an important structural and transport membrane molecule, protein band 3. Band 3 is a ubiquitous protein. It is present in cell, nuclear, Golgi, and mitochondrial membranes. Band 3 is the most heavily used anion exchanger in the human body because of its crucial role in respiration and acid-base balance. Senescent cell antigen has been localized to band 3 residues 538-554 and 812-827, using competitive inhibition studies with synthetic peptides of band 3 to absorb the IgG isolated from senescent erythrocytes and immunoblotting studies. In mammalian brain, band 3 performs the same functions as that of erythroid band 3. These functions are anion transport, ankyrin binding, and generation of senescent cell antigen, an aging antigen that terminates the life of cells. Our results suggest that the transport domain of erythroid and neural band 3 are similar functionally and structural. This supports the hypothesis that the immunological mechanism of maintaining homeostasis is a general physiologic process for removing senescent and damaged cells in mammals and other vertebrates.