Healthy lifestyle, metabolomic signature, and risk of late-onset schizophrenia: evidence from the prospective cohort

A healthy lifestyle is associated with a reduced risk of schizophrenia, but the underlying metabolic mechanisms remain unclear. The aim of this study was to identify a metabolomic signature of a healthy lifestyle, to assess its mediation between lifestyle and schizophrenia risk, and to evaluate its potential causal link to schizophrenia. This study included 170,783 participants from the UK Biobank with comprehensive data on lifestyle, metabolomics, and relevant covariates. An elastic net regression model was employed to construct a metabolomic signature reflecting a healthy lifestyle. Associations between this signature and schizophrenia risk were examined using Cox proportional hazards models. Mediation analysis was conducted to assess the mediating role of the metabolomic signature in the association between healthy lifestyle and schizophrenia onset, while Mendelian randomization (MR) analysis was performed to explore potential causal effects. Individuals with a healthy lifestyle had a 58% lower risk of schizophrenia compared to those with an unhealthy lifestyle (HR 0.42; 95% CI, 0.29-0.61). The metabolomic signature, comprising 113 metabolites, was strongly correlated with the healthy lifestyle (r = 0.36, P < 0.001) and associated with reduced schizophrenia risk (HR 0.62 per SD increase; 95% CI, 0.49-0.79). This signature accounted for 15.59% of the association between healthy lifestyle and schizophrenia risk, and MR analysis suggested a possible causal relationship. Our study revealed a potential link between healthy lifestyle, metabolomic signature, and late-onset schizophrenia, highlighting the potential role of lifestyle-related metabolic alterations in schizophrenia development.