Plasma Proteomic Signature of Frailty in 50,506 Adults

Proteomics enables systematic elucidation of the biological mechanisms underlying health states including frailty. Here, through a large-scale proteome-wide association study (PWAS) encompassing 2,911 plasma proteins in 50,506 UK Biobank participants, we identified 1,339 proteins significantly associated with frailty, revealing novel functional modules implicated in frailty pathogenesis, particularly the one characterized by the collagen-containing extracellular matrix and vesicle lumen pathways. Replication analyses in an independent external cohort (TwinGene study) confirmed partial but consistent associations at both protein and pathway levels, supporting the reliability of these findings. Mendelian randomization analyses supported causal associations of 50 proteins with frailty. Protein-protein interaction network and expression quantitative trait loci analyses revealed MMP1 and LGALS8 serving as hub proteins. Moreover, we developed a novel proteome-based frailty measure, termed as Proteomic Frailty Score (PFS), which demonstrated robust predictive performance (C-index > 0.7) for 198 (30.2% = 198/655) incident diseases across 13 categories and broad responsiveness to 85 modifiable risk factors. Incorporating PFS into a conventional risk factors model significantly improved the predictive performance for 510 (77.9% = 510/655) incident diseases. Longitudinal analyses with three assessments (n∼1000) revealed an accelerated progression of the PFS with advancing age and increasing baseline frailty severity. To facilitate public use, we further created a publicly accessible online tool for PFS calculation ( https://zipoa.shinyapps.io/frailty/ ). Finally, we observed a biphasic pattern of frailty-associated proteomic dysregulation across lifespan, with peak transitions occurring at approximately ages 50 and 63, implicating distinct biological pathways. Together, we establish PFS as a robust biomarker of biological aging while identifying critical windows and molecular targets for interventions against frailty progression.