Physiologic autoantibodies are part of our normal immune repertoire where they function to maintain homeostasis by performing physiologic functions. The role of physiologic autoantibodies in removing senescent and damaged cells is probably the best example of a physiologic autoantibody, complete with well established function. IgG autoantibodies bind to altered band 3 anion exchanger protein on senescent cells and trigger their removal by macrophages. Band 3 isoforms are found in all cells, tissues, and membranes, and in all species examined. In this paper, we discuss the innate immune response to band 3 membrane proteins and their regulation of cellular lifespan. The role of physiologic autoantibodies and their peptide antigens in health and disease, apoptosis, and their therapeutic potential is discussed focusing on the examples of senescence and malaria.