The brain structure, immunometabolic and genetic mechanisms underlying the association between lifestyle and depression

Abstract Lifestyle factors have been acknowledged to be modifiable targets that can be used to counter the increasing prevalence of depression. This study aims to investigate combining an extensive range of lifestyle factors, including alcohol consumption, diet, physical activity, sleep, smoking, sedentary behavior and social connection, that contribute to depression, and examine the underlying neurobiological mechanisms. Over nine years of follow-up, a multivariate Cox model was utilized on 287,282 participants from UK Biobank to demonstrate the protective roles of seven lifestyle factors and combined lifestyle score on depression. Combining genetic risk and lifestyle category in 197,344 participants, we found that a healthy lifestyle decreased the risk of depression across a population with varied genetic risk. Mendelian randomization confirmed the causal relationship between lifestyle and depression. A broad range of brain regions and peripheral biomarkers were related to lifestyle, including the pallidum, the precentral cortex, triglycerides and C-reactive protein. Structural equation modeling on 18,244 participants revealed underlying neurobiological mechanisms involving lifestyle, brain structure, immunometabolic function, genetics and depression. Together, our findings suggest that adherence to a healthy lifestyle could aid in the prevention of depression.