Our current studies focus on the molecular changes induced by aging. During aging, changes in proteins occur that alter their function and render them immunogenic. These “neoantigen” are recognized by physiologic autoantibodies. Physiologic autoantibodies and their corresponding antigens offer therapeutic strategies for disease intervention through the innate immune response. Early studies done in the 1970s showed humans and animals to have physiologic antibodies that bind to a neoantigen called senescent cell antigen (SCA), which appears on senescent and damaged cells and initiates their removal by macrophages. These studies led to the discovery that oxidation can generate a new antigen in situ. Oxidation accelerated aging of red cells, generated SCA and IgG binding, and triggered removal of red cells by macrophages. Since then, a number of laboratories have found that oxidation can generate other neoantigens. For example, oxidized LDL (OxLDL) induces antibodies that can modify the natural progression of atherosclerosis. Apoptotic cells express oxidatively modified moieties on their surfaces that are involved in macrophage recognition and phagocytosis. Physiologic autoantibodies were used to isolate SCA from brain tissue. HPLC and fast atom bombardment ionization mass spectrometry (FAB-MS) of the isolated antigen suggested that the aging antigen is a subset of band 3, a family of proteins also called anion exchange proteins (AE1–3). FAB-MS results indicate that residues matching all three band 3 isoforms (AE1, AE2, and AE3) are detected in aging antigen fractions. Among the fragments identified with FAB-MS was a sequence corresponding to an aging epitope, human band 3 sequence LFKPPKYHPDVPYVKR, residue 812–830 in AE1; HHPDVTYVK, residue 1144–1152 in AE2; or HHPEQPYVTK, residue 1135–1144 in AE3. A residue that is close to that region was identified in mouse AE1 ASGPGAAAQIQEVK, residue 762–775. The potential for altering the natural progression of diseases using select peptide-defined epitopes within or overlapping the aging antigenic site (547–553 and 824–829) is discussed using the innate immune response to band 3 in malaria as an example.