Proteomic signatures of systemic inflammation in aging, multimorbidity, and mortality.
BACKGROUND Chronic low-grade inflammation is central to biological aging, but routine inflammatory biomarkers capture limited molecular heterogeneity. We aimed to develop a proteomic inflammaging score (PIS) and evaluate its practical utility. METHODS In 40,471 England participants from UK biobank, we used LASSO to identify proteins associated with six inflammatory biomarkers (CRP, SII, SIRI, MLR, NLR, PLR), and validated them in 5250 non-England cohort. Deep neural networks generated biomarker-specific scores, integrated into PIS via elastic-net Cox regression. We evaluated associations with mortality, age-related diseases, and aging biomarkers, and compared predictive utility (C-index, NRI, IDI) against conventional markers. DE-SWAN analysis was used to characterize nonlinear age-related proteomic changes, and genetics analyses were performed to investigate genetic architecture. RESULTS A total of 1112 proteins were identified to associated with all six inflammation biomarkers and 93 proteins retained in simplified versions. Both full (HR = 1.88, 95%CI: 1.79-1.98) and simplified (HR = 1.88, 95%CI: 1.79-1.97) PIS were positively associated with all-cause mortality and multiple aging-related phenotypes. PISs outperformed conventional inflammatory and aging biomarkers, significantly improving mortality prediction: for all-cause mortality, clinical indices plus simplified PIS achieved a C-index of 0.758 (95% CI, 0.752-0.765). External validation in the non-England cohort showed comparable predictive performance. Proteomic inflammation crests were near ages 50, 62-63 and 67 years. 25 lead SNPs were associated with PIS, linking PIS to inflammatory traits and aging biomarkers. CONCLUSION PIS provides a compact, interpretable proteomic measure of inflammaging and captures mortality, multisystem disease burden, and aging-related biology in population-scale cohorts.