Accelerated biological aging underlies the link between heavy metal mixture exposure and depression: A multi-omics...

Growing evidence implicates accelerated biological aging in environmentally induced psychiatric disorders, yet its role in metal-associated depression remains unclear. Using NHANES data, we evaluated associations between heavy metal mixtures and depression. Bidirectional mediation analysis was used to assess reciprocal pathways linking heavy metals, biological aging, and depression. Simultaneously, candidate genes linking heavy metal exposure to depression and biological aging were identified by mining the Comparative Toxicogenomics Database, analyzing differentially expressed genes (DEGs) from the Gene Expression Omnibus, and integrating the resulting evidence within a toxicogenomic framework to explore potential molecular mechanisms. The prevalence of depression among participants was 8.66 %. Metal mixtures significantly increased depression risk. Notably, cadmium and antimony increased the risk of depression (OR: 1.52, 95 % CI: 1.19, 1.94 and OR: 1.54, 95 % CI: 1.22, 1.93). Both metals have low thresholds (0.227 μg/L and 0.053 μg/L, respectively). Additionally, lead, cobalt, and molybdenum showed positive associations in specific models. Although population-level exposure to heavy metals declined from 1999 to 2020, concentrations remained sufficient to elevate depression risk. Our correlation analysis also identified a strong correlation between PhenoAge and chronological age (r = 0.84, P < 0.001). Mechanistically, we found that accelerated PhenoAge partially mediated the associations of several metals with depression risk, including monomethylarsonic acid (β = 0.004; 95 %CI: 0.003,0.006), cadmium (β = 0.006; 95 %CI: 0.003, 0.010), lead (β = 0.009; 95 %CI: 0.006, 0.011), cobalt (β = 0.010; 95 %CI: 0.006, 0.013), molybdenum (β = 0.009; 95 %CI: 0.006, 0.011), and antimony (β = 0.008; 95 %CI: 0.005, 0.011). Pathway analysis and DEGs implicated the contribution of neurodegeneration-multiple diseases pathway, with core molecular targets centering on BDNF, IL6, GSK3B, PTGS2, and SOD1. These findings, which imply biological aging as a potential link between metal exposure and depression, call for revised safety thresholds and pinpoint molecular targets for intervention.