Background: Although healthy lifestyle has been linked with a reduced risk of cardiovascular diseases (CVDs), the potential metabolic mechanism underlying this association remains unknown. Methods: We included 161,018 CVD-free participants from the UK Biobank. Elastic net regression was utilized to generate a healthy lifestyle-related metabolic signature. The Cox proportional hazards model was applied to investigate associations of lifestyle-related metabolic signature with incident CVDs, and mediation analysis was conducted to evaluate the potential mediating role of metabolic profile on the healthy lifestyle-CVD association. Mendelian randomization (MR) analysis was conducted to detect the causality. Results: During 13 years of follow-up, 17,030 participants developed incident CVDs. A healthy lifestyle-related metabolic signature comprising 123 metabolites was established, and it was inversely associated with CVDs. The hazard ratio (HR) was 0.83 (95% confidence interval [CI]: 0.81, 0.84) for CVD, 0.83 (95% CI: 0.81, 0.84) for ischemic heart disease (IHD), 0.86 (95% CI: 0.83, 0.90) for stroke, 0.86 (95% CI: 0.82, 0.89) for myocardial infarction (MI), and 0.75 (95% CI: 0.72, 0.77) for heart failure (HF) per standard deviation increase in the metabolic signature. The metabolic signature accounted for 20% of the association between healthy lifestyle score and CVD. Moreover, MR showed a potential causal association between the metabolic signature and stroke. Conclusions: Our study revealed a potential link between a healthy lifestyle, metabolic signatures, and CVD. This connection suggests that identifying an individual’s metabolic status and implementing lifestyle modifications may provide novel insights into the prevention of CVD.

Background: Published studies have documented the association between sunshine duration and depression symptoms; however, the evidence regarding the long-term effects and potential mechanisms remains insufficient. This study aimed to examine the association between sunshine duration and incident depression and to explore potential mediating pathways. Methods: A total of 336,805 participants from the UK Biobank were included in the study. Meteorological exposures were estimated using the bilinear interpolation approach and time-weighted method. The association between sunshine duration and incident depression was examined through the time-dependent Cox proportional hazard model and generalized propensity score model. Vitamin D, calcium, immune biomarkers, an aggregated inflammation score (INFLA-score), and sleep pattern were selected as the potential mediators. Causal mediation analysis was employed to elucidate underlying mediating effects. Results: With a median follow-up of 13 years, 13,862 cases of incident depression were identified. Sunshine duration demonstrated a negative association with the incident depression. The effects were stronger among the elderly, alcohol consumers, individuals who spent less time outdoors, and those who were less physically active. Vitamin D, calcium, INFLA, neutrophils, and monocytes emerged as the top five contributors of immune biomarkers to the natural indirect effect. The combined mediating effect of top five biomarkers and sleep pattern accounted for 30% of the total effect of sunshine duration on the incident depression. Conclusion: Our study suggests that longer sunshine duration might mitigate depression through vitamin D-related metabolism, inflammation, and sleep pattern. It may serve as an effective natural antidepressant, particularly for the elderly, alcohol consumers, less outdoor spenders, and those who were less physically active.