Immunotherapy targeting isoDGR‐protein damage extends lifespan in a mouse model of protein deamidation

Aging results from the accumulation of molecular damage that impairs normal biochemical processes. We previously reported that age‐linked damage to amino acid sequence NGR (Asn‐Gly‐Arg) results in “gain‐of‐function” conformational switching to isoDGR (isoAsp‐Gly‐Arg). This integrin‐binding motif activates leukocytes and promotes chronic inflammation, which are characteristic features of age‐linked cardiovascular disorders. We now report that anti‐isoDGR immunotherapy mitigates lifespan reduction of Pcmt1 −/− mouse. We observed extensive accumulation of isoDGR and inflammatory cytokine expression in multiple tissues from Pcmt1 −/− and naturally aged WT animals, which could also be induced via injection of isoDGR‐modified plasma proteins or synthetic peptides into young WT animals. However, weekly injection of anti‐isoDGR mAb (1 mg/kg) was sufficient to significantly reduce isoDGR‐protein levels in body tissues, decreased pro‐inflammatory cytokine concentrations in blood plasma, improved cognition/coordination metrics, and extended the average lifespan of Pcmt1 −/− mice. Mechanistically, isoDGR‐mAb mediated immune clearance of damaged isoDGR‐proteins via antibody‐dependent cellular phagocytosis (ADCP). These results indicate that immunotherapy targeting age‐linked protein damage may represent an effective intervention strategy in a range of human degenerative disorders. Synopsis Anti‐isoDGR immunotherapy enhances the healthspan of naturally aged mice and extends the lifespan of Pcmt1 KO mice by reducing chronic inflammation. The health benefit is mediated by immune clearance of damaged proteins by antibody‐dependent cellular phagocytosis (ADCP). Age‐linked isoDGR protein damage induces chronic inflammation and tissue degeneration. The isoDGR triggered pathology is mitigated by anti‐isoDGR immunotherapy. The treatment decreases isoDGR‐protein levels, lowers pro‐inflammatory cytokines, increase body weight, improves cognition, and extends lifespan in Pcmt1 KO mice. The immunotherapy clears damaged isoDGR‐proteins through antibody‐dependent cellular phagocytosis. Graphical Abstract Anti‐isoDGR immunotherapy enhances the healthspan of naturally aged mice and extends the lifespan of Pcmt1 KO mice by reducing chronic inflammation. The health benefit is mediated by immune clearance of damaged proteins by antibody‐dependent cellular phagocytosis (ADCP).