The associations of multiple metals mixture with accelerated DNA methylation aging

Aging is a leading cause of mortality for the elderly and DNA methylation age is reported to be predictive of biological aging. However, few studies have investigated the associations between multiple metals exposure and accelerated aging in the elderly. We performed a pilot study of 288 elderly participants aged 50-115 years and measured genome-wide DNA methylation and 22 blood metals concentrations. Measures of DNA methylation age were estimated using CpGs from Illumina HumanMethylation EPIC BeadChip. Linear mixed regression and Bayesian kernel machine regression (BKMR) models were used to estimate the individual and overall associations between multiple metals and accelerated methylation aging. Single metal models revealed that each 1-standard deviance (SD) increase in log-transformed vanadium, cobalt, nickel, zinc, arsenic, and barium was associated with a -2.256, -1.318, 1.004, -1.926, 1.910 and -1.356 changes in ΔAge, respectively; meanwhile, for aging rate, the change was -0.019, -0.013, 0.010, -0.018, 0.023, and -0.012, respectively (all P < 0.05). The BKMR models showed reverse U-shaped associations of the overall metals mixture with ΔAge and aging rate. Downward trends of ΔAge and aging rate were observed for increasing quantiles of essential metals mixture, but upward trends were observed for non-essential metals mixture. Further individual analysis of the BKMR revealed that the 95% confidence interval of ΔAge and aging rate associated with vanadium, zinc, and arsenic did not cross 0, when other metals concentrations set at 25th, 50th, and 75th percentile. Our findings suggest reverse U-shaped associations of the overall metals mixture with accelerated methylation aging for the first time, and vanadium, zinc, and arsenic may be major contributors driving the associations.