Chronic low-grade inflammation is increasingly recognized as a key factor in biological aging. Traditional inflammatory biomarkers often fail to capture the full molecular complexity of this process. In this study, researchers aimed to develop a novel proteomic inflammaging score (PIS) to better evaluate systemic inflammation’s impact on aging and mortality.
The study utilized data from 40,471 participants in the UK Biobank, employing LASSO regression to identify proteins associated with six established inflammatory biomarkers: C-reactive protein (CRP), Systemic Immune-Inflammation Index (SII), Systemic Inflammation Response Index (SIRI), Monocyte-to-Lymphocyte Ratio (MLR), Neutrophil-to-Lymphocyte Ratio (NLR), and Platelet-to-Lymphocyte Ratio (PLR). The findings were validated in a separate cohort of 5,250 participants.
Deep neural networks were used to generate biomarker-specific scores, which were then integrated into the PIS using elastic-net Cox regression. The researchers evaluated the associations between the PIS and various health outcomes, including mortality, age-related diseases, and other aging biomarkers. They also compared the predictive utility of the PIS against conventional markers using metrics such as C-index, Net Reclassification Improvement (NRI), and Integrated Discrimination Improvement (IDI).
A total of 1,112 proteins were identified as being associated with the six inflammatory biomarkers, with 93 proteins retained in simplified versions of the PIS. Both the full and simplified PIS demonstrated a positive association with all-cause mortality and multiple aging-related phenotypes. Notably, the simplified PIS significantly improved mortality prediction, achieving a C-index of 0.758 when combined with clinical indices.
External validation in the non-England cohort showed comparable predictive performance, reinforcing the robustness of the PIS. The study also identified specific age-related peaks in proteomic inflammation, occurring around ages 50, 62-63, and 67 years. Furthermore, 25 lead single nucleotide polymorphisms (SNPs) were associated with the PIS, linking it to both inflammatory traits and aging biomarkers.
In conclusion, the PIS provides a compact and interpretable measure of inflammaging, capturing the complex interplay between systemic inflammation, mortality, and multisystem disease burden in large population-scale cohorts.