Plasma proteins associated with disability and mortality risks in Japanese community-dwelling octogenarians

Japan has one of the world's longest life expectancies, yet biomarkers associated with disability and mortality in very old adults remain uncertain. The goal of this study was to identify plasma proteins associated with incident disability and mortality in community-dwelling octogenarians. Two prospective cohorts were analyzed: the Kawasaki Aging Well-being Project (KAWP; 2017-2018; 4.5-year follow-up) as discovery and Invecchiare in Chianti (InCHIANTI; 1998-2000; 15-year follow-up) for external replication. The discovery sample comprised 230 disability-free adults aged 85-89 years (50.4% women). Twenty-nine plasma proteins were assayed using Luminex xMAP. Associations with incident disability and mortality were estimated with elastic net-regularized Cox models and tested in multivariable Cox models in the full KAWP cohort and in InCHIANTI. Higher beta-2-microglobulin and cystatin C levels were associated with an increased risk of disability (hazard ratio [HR] 1.35, 95% confidence interval [CI] 1.11-1.64; HR 1.42, 95% CI 1.14-1.76). For mortality, epidermal growth factor was inversely associated (HR 0.51, 95% CI 0.27-0.96), while interferon gamma-induced protein 10 was positively associated (HR 1.23, 95% CI 1.06-1.44). Associations with disability were broadly replicated in the full KAWP cohort and among InCHIANTI participants aged ≥ 80 years, whereas mortality-related findings were not replicated. In conclusion, beta-2-microglobulin and cystatin C may serve as biomarkers of future disability. These patterns implicate kidney dysfunction and inflammation as drivers of health decline in very old adults and support early risk stratification to guide preventive interventions.