Accelerated Biological Aging and Schizophrenia Risk: Evidence from the UK Biobank

BACKGROUND AND HYPOTHESIS: Schizophrenia is a chronic psychiatric disorder with increased morbidity and mortality. Emerging evidence links biological aging to schizophrenia, but large-scale population-based studies integrating mechanistic and causal analyses remain limited. STUDY DESIGN: Leveraging UK Biobank data, we examined the association between two biological aging markers-Klemera-Doubal Method Age (KDMAge) and PhenoAge acceleration-with schizophrenia risk using cross-sectional and prospective analyses. Mediation analyses assessed inflammatory, metabolic, vitamin/mineral, and endocrine pathways. Bidirectional Mendelian randomization (MR) was applied to explore causality. STUDY RESULTS: Accelerated biological aging was significantly associated with increased schizophrenia risk in cross-sectional (KDMAge acceleration: odds ratio [OR] = 1.27, 95% CI: 1.06-1.53, P = .010; PhenoAge acceleration: OR = 1.87, 95% CI: 1.49-2.33, P < .001) and prospective analyses (KDMAge acceleration: hazard ratio [HR] = 1.53, 95% CI: 1.19-1.97, P = .001; PhenoAge acceleration: HR = 2.77, 95% CI: 2.07-3.71, P < .001). Stratified analyses indicated effect modification by BMI and socioeconomic status. Mediation analyses identified inflammatory markers, particularly neutrophil count and vitamin D as partial mediators. Forward MR supported a potential causal effect of genetically predicted KDMAge acceleration on schizophrenia risk (OR IVW = 1.48, P = .029), whereas reverse MR findings were less robust. CONCLUSIONS: These findings provide epidemiological and genetic evidence that accelerated biological aging is associated with schizophrenia. Interventions targeting chronic inflammation, vitamin D supplementation, and lifestyle adjustments to improve metabolic health may slow biological aging and reduce schizophrenia risk.