Unravelling the crucial aging signatures linking cadmium exposure with the risk of frailty and mortality: DNA methylation aging clocks, biological aging indicators, or telomere length?

• Cadmium exposure was associated with risk of mortality and frailty in a 20-year cohort study. • We both assessed participants’ frailty, and the mortality risk of all-cause, cardiovascular diseases, and cancer. • Multidimensional aging signatures were assessed to reveal the above associations. • Participants can be categorized into four aging-featured clusters. We aimed to investigate whether heavy metal exposure is associated with aging acceleration and aging-related outcomes, and whether aging mediates such associations. 6,583 participants from a 20-year nationally representative cohort study were included. Blood levels of two typical heavy metals, cadmium (Cd) and lead (Pb), were measured. Eleven aging signatures were assessed, including DNA methylation aging clocks, biological aging indicators, and telomere length. Survey-weighted Cox proportional hazard models, generalized linear models, and logistic regression models were used to evaluate the effects of metals on aging and related outcomes. An unsupervised machine learning algorithm was applied to identify aging-featured clusters. The role of aging acceleration in metal-associated frailty and mortality was tested using average causal mediation effect analysis. We found that Cd was associated with both frailty and mortality risk, and Pb was associated with mortality risk. Significant associations with multiple aging signatures were mainly observed for Cd exposure. Participants were categorized into four clusters. Finally, aging signatures mediated Cd-associated frailty and mortality with mediation proportions ranging from 4.37% to 43.61%. Our findings reveal that Cd exposure is associated with aging acceleration, frailty, and mortality risk. Aging mediated the Cd-associated frailty and mortality, which highlights the potential mechanisms and prevention avenues.