Antibody targeting of aging damaged isoDGR-proteins doubles lifespan in a mouse model of chronic inflammation

Abstract

ABSTRACTAging is the result of the accumulation of molecular damages that impair normal biochemical activities. We previously reported that aging-damaged amino acid sequence NGR (Asn-Gly-Arg) results in a ‘gain-of-function’ conformational switching to isoDGR (isoAsp-Gly-Arg) motif. This integrin-binding motif activates leukocytes to induce chronic inflammation, which are characteristic features of age-linked cardiovascular disorders. We now report that anti-isoDGR immunotherapy doubles lifespan in mouse model of chronic inflammation. We observed extensive accumulation of isoDGR and inflammatory cytokine expression in multiple tissues from Pcmt1-KO and old 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 (1mg/kg) was sufficient to significantly reduce isoDGR-modified proteins and pro-inflammatory cytokine expression, improve behaviour and coordination, and double the average lifespan of Pcmt1-KO mice. Mechanistically, isoDGR-mAb mediated the immune clearance of damaged isoDGR-proteins by antibody-dependent cellular phagocytosis. These results indicate that immunotherapy targeting aging-damaged proteins may represent effective interventions for a range of age-linked degenerative disorders.Graphical AbstractAnti-isoDGR immunotherapy induces immune clearance of aging damaged isoDGR-proteins to reduce chronic inflammation, improve behaviour and coordination, and double lifespan in PCMT-/-mice.