The Association between Frailty and Inflammatory Biomarkers in the Elderly

TL;DR

This study finds that blood markers of inflammation are linked to frailty in older adults, suggesting potential targets for treatment.

Contribution

The study identifies causal links between inflammatory proteins and frailty using proteogenomic integration and Mendelian randomization.

Findings

NLR, dNLR, and HRR are independent predictors of frailty.

Elevated IL-6 and TNF-α are associated with frailty.

JAK-STAT signaling is enriched in inflammation-driven frailty.

Abstract

This study aims to characterize associations between frailty and systemic inflammation using blood-derived indices and cytokines, and identify causal mechanisms through proteogenomic integration.

We analyzed neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), monocyte-to-lymphocyte ratio (MLR), and hemoglobin-to-red cell distribution width ratio (HRR) from routine blood tests. Serum interleukin-6 (IL-6), IL-1β, IL-18, and tumor necrosis factor-α (TNF-α) were quantified. Mendelian randomization (MR) integrated plasma proteome-wide genome-wide association study (GWAS) data (N = 54,219) with UK Biobank frailty genetics (n = 175,226) for causal inference. Functional annotation of differentially expressed proteins employed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses.

Adjusted analyses identified NLR (OR = 1.57, 95%CI=1.07–2.30), dNLR (OR = 1.59, 1.11–2.27), and HRR (OR = 0.13, 0.03–0.44) as independent frailty predictors. Elevated IL-6 (OR = 1.14, 1.01–1.30) and TNF-α (OR = 1.21, 1.07–1.36) correlated with frailty. MR revealed 26 plasma proteins causally linked to frailty, including five inflammation-associated proteins. Pathway analysis demonstrated JAK-STAT signaling enrichment, connecting chronic inflammation to frailty pathogenesis.

NLR, dNLR and HRR serve as accessible frailty biomarkers, while IL-6 and TNF-α are cytokine drivers of frailty. The MR-validated plasma proteome implicates JAK-STAT axis activation as a key mechanism driving inflammation-associated frailty, providing therapeutic targets for this geriatric syndrome.