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

Nov 27, 2025Schizophrenia bulletin

Faster Biological Aging Linked to Higher Risk of Schizophrenia in UK Biobank Participants

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Abstract

Accelerated biological aging is significantly associated with increased schizophrenia risk, with PhenoAge acceleration showing an odds ratio of 1.87.

Both KDMAge and PhenoAge accelerations are linked to heightened schizophrenia risk in cross-sectional and prospective analyses.
KDMAge acceleration has an odds ratio of 1.27 in cross-sectional studies and a hazard ratio of 1.53 in prospective studies.
PhenoAge acceleration has an odds ratio of 1.87 in cross-sectional studies and a hazard ratio of 2.77 in prospective studies.
Mediation analyses suggest inflammatory markers, particularly neutrophil count and vitamin D, partially mediate the relationship between biological aging and schizophrenia.
Bidirectional Mendelian randomization indicates a potential causal effect of genetically predicted KDMAge acceleration on schizophrenia risk.

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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.

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

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