Three generations of epigenetic clocks in mediating the adverse effect of smoking on metabolic health

Metabolic syndrome (MetS) is a composite disorder that includes abdominal obesity, impaired glucose levels, high blood pressure, and dyslipidemia. Smoking can alter epigenetic profiles and is a critical modifiable risk factor for MetS. We aim to explore the epigenetic age acceleration (EAA) that can mainly deliver smoking influences on metabolic health. We conducted a mediation analysis of 2,474 individuals with data in the Taiwan Biobank. Current and former smoking and the respective pack-years were included as four exposure factors. Seven markers of DNA methylation (DNAm) covering three generations of epigenetic clocks were included as mediators. Seven metabolic outcomes included MetS status (yes vs. no) and six related traits. GrimEAA and DunedinPACE mediated the associations of the four smoking factors with MetS, fasting glucose, triglyceride, and high-density lipoprotein cholesterol levels (false discovery rate < 0.05). GrimEAA and DunedinPACE respectively mediated 48.2% and 24.2% of current smoking’s effect on MetS and 60.9% and 26.1% of current smoking pack-year’s effect on MetS risk. The DNAm plasminogen activator inhibitor 1 level mediated the adverse effects of current smoking status and pack-years on all seven metabolic outcomes. The GrimEAA-mediated proportions were approximately two times greater than the DunedinPACE-mediated proportions.