Threshold and combined effects of heavy metals on the risk of phenotypic age acceleration among U.S. adults

Accumulation of heavy metals in the body has been shown to affect the phenotypic age (PhenoAge). However, the combined and threshold effects of blood heavy metals on the risk of PhenoAge acceleration (PhenoAgeAccel) are not well understood. A cross-sectional study was conducted using blood heavy metal data (N = 7763, age ≥18 years) from the 2015-2018 National Health and Nutrition Examination Survey. PhenoAgeAccel was calculated from actual age and nine biomarkers. Multiple regression equations were used to describe the relationship between heavy metals and PhenoAgeAccel. Least Absolute Shrinkage and Selection Operator (LASSO) regression modeling was used to explore the relationship between the combined effects of heavy metals and PhenoAgeAccel. Threshold effect and multiple regression analyses were performed to explore the linear and nonlinear relationships between heavy metals and PhenoAgeAccel. Threshold effect analysis showed that blood mercury (Hg) concentration was linearly associated with PhenoAgeAccel. In contrast, lead (Pb), cadmium (Cd), manganese (Mn), and combined exposure were nonlinearly associated with PhenoAgeAccel. In addition, the combination of Pb, Cd, Hg, and Mn significantly affected PhenoAgeAccel. The risk of PhenoAgeAccel was increased by 207% (P < 0.0001). Meanwhile, a threshold relationship was found between blood Pb, Cd, Mn, and the occurrence of PhenoAgeAccel. Overall, our results indicate that combined exposure to heavy metals may increase the risk of PhenoAgeAccel. This study underscores the need to reduce heavy metal pollution in the environment and provides a reference threshold for future studies.