Age-linked lung pathology is reduced by immunotherapeutic targeting of isoDGR protein damage

Advancing age is the primary risk factor for pulmonary diseases. Our investigation revealed an 8-fold increase in aging induced isoDGR-damaged proteins in lung tissue from human pulmonary fibrosis patients compared to healthy tissues, accompanied by elevated frequencies of CD68+/CD11b+ macrophages, indicating lung tissue is susceptible to time-dependent accumulation of isoDGR-proteins. To elucidate the mechanisms through which isoDGR-proteins may exacerbate aging lung disorders for potential therapeutic targeting, we assessed the functional role of this isoDGR-motif in naturally-aged mice and mice lacking the corresponding isoDGR repair enzyme (Pcmt1-/-). IsoDGR-protein accumulation in mouse lung tissue and blood vessels correlated with chronic low-grade inflammation, pulmonary edema, and hypoxemia. IsoDGR accretion induced mitochondrial and ribosomal dysfunctions, cellular senescence, and apoptosis, contributing to progressive lung damage over time. Treatment with anti-isoDGR antibodies suppressed TLR pathway activity, mitigated cytokine-driven inflammation, restored mtDNA expression, and significantly reduced lung pathology in-vivo. Similarly, exposure of lung endothelial cells to isoDGR-modified fibronectin impaired oxygen consumption, increased reactive oxygen species levels, and disrupted acidification, but these effects were efficiently reversed by target-specific antibody therapy. Collectively, our findings underscore the significant contribution of isoDGR-damaged proteins to age-linked lung pathology. IsoDGR-specific therapy emerges as a promising treatment approach for pulmonary disorders in older patients. ### Competing Interest Statement The authors have declared no competing interest.