The way that males and females react to environmental exposures and negative impacts on their neurological systems is often different. Although previous research has examined the cognitively impairing effects of solitary metal exposures, the relationship between metal mixtures and cognitive function, particularly when considering an individual’s sex, remains elusive. This study aimed to investigate the sex differences in the association between multiple metal combinations and cognitive function in older Americans. This research employed the 2011–2014 NHANES survey of elderly Americans. The association between five mixed metals and four cognitive tests (the animal fluency test (AFT), the digit symbol substitution test (DSST), the instant recall test (IRT), and the delayed recall test (DRT)) were investigated with generalized linear regression model (GLM), Bayesian kernel machine regression model (BKMR), weighted quantile sum regression model (WQS), and quantile g-computation regression model (Qgcomp). A total of 1833 people, including 883 males and 950 females, enrolled in this cross-sectional study. We discovered that blood lead and blood cadmium were negatively associated with cognitive performance, while blood selenium demonstrated a positive association with cognitive function in older people. The negative relationship of heavy metal combinations on cognitive function might be somewhat reduced or even reversed via selenium. The IRT, AFT, and DSST are three of the four cognitive tests where men had more dramatic positive or negative results. There was a sex-specific connection between blood metal ratios and cognitive function among older Americans, as evidenced by the more significant relationship between mixed metals and cognitive performance in men (either positively or negatively). These results emphasize the impacts of ambient heavy metal exposure on cognitive function by employing sex-specific methods.

Background: The World Health Organization (WHO) developed an assessment for healthy aging termed intrinsic capacity (IC). However, the association between IC and depression/anxiety remains poorly understood, with limited understanding of the underlying metabolic mechanisms. Methods: This prospective cohort study comprised 212,033 UK Biobank participants recruited between 2006 and 2010. We calculated a UK Biobank-adapted four-domain IC deficit score using seven functional status indicators across psychological, sensory, vitality, and locomotor domains. Elastic net regression was employed to derive a metabolic signature that represented IC status. Polygenic risk scores (PRS) for depression and anxiety were computed from associated risk variants. Results: Compared with a 0 IC deficit score, participants with a 4+ score had higher risk, with hazard ratios (HRs) (95% CIs) of 3.96 (3.72–4.21) for depression and 3.03 (2.82–3.25) for anxiety. The metabolic signature of IC comprised 59 metabolites, with mediation effects of 1.007 (1.005, 1.008) for depression and 1.006 (1.004, 1.007) for anxiety. The highest hazards were observed in participants with high PRS and 4+ IC score; the HRs were 4.36 (3.70–5.13) for depression and 3.46 (2.87–4.17) for anxiety. Conclusions: IC is associated with a higher risk of depression and anxiety, possibly mediated by its metabolic signature, with enhanced effects in genetically susceptible individuals.