Epigenetic clocks are markers of biological ageing that may vary in their sensitivity to environmental and lifestyle exposures. To evaluate their utility as sensors of the human exposome, we investigated responses to two biologically relevant exposures with contrasting effects, the Mediterranean die and smoking.

We assessed the sensitivity of eleven epigenetic clocks to diet and smoking and evaluated whether Mediterranean diet adherence modifies associations between smoking and epigenetic ageing.

We analysed 928 participants (mean age 41 years, 59% male) from the Airwave Health Monitoring Study. Linear regression models assessed associations of Mediterranean Diet Score (MDS), smoking status, and blood cotinine with epigenetic age acceleration (EAA). Smoking status × MDS interactions tested whether smoking-related EAA differed by Mediterranean diet adherence. Models were adjusted for demographic, socioeconomic, lifestyle, and psychological covariates.

Higher MDS was associated with lower EAA for GrimAge (β = −0.07 SD; 95% CI: −0.13, −0.01) and Bernabeu (β = −0.08 SD; 95% CI: −0.14, −0.02) after false discovery rate correction. Smoking was strongly associated with increased EAA, particularly for GrimAge, Bernabeu, and DunedinPACE. Among current smokers, effect sizes were greater in those with lower dietary adherence (e.g. GrimAge: 1.79 SD, 95% CI: 1.54, 2.04) compared with those with higher adherence (1.35 SD, 95% CI: 1.01, 1.68; P_ _interaction < 0.001). Similar attenuation patterns were observed for Bernabeu. Fruit, vegetable, and whole-grain intakes were the components most consistently associated with attenuation of smoking-related EAA.

Our findings indicate that certain epigenetic clocks can capture the combined influence of harmful and protective exposures within the exposome. Rather than suggesting that diet neutralises the risks of tobacco, these results demonstrate variation in molecular ageing signals associated with both nutrition and environmental toxins, highlighting the potential value of second-generation clocks for quantifying resilience-related biological variation.