Alcohol Consumption and DNA Methylation in a Mediterranean Cohort: A Focus on Oxidative Stress and Aging Biomarkers

There is considerable interest in the connection between alcohol-induced oxidative stress, DNA methylation, antioxidants, and accelerated aging across diverse populations. Nevertheless, self-reported alcohol consumption is prone to bias, and objective biomarkers of alcohol intake are needed. Our aims were to investigate the performance of an epigenomic biomarker of alcohol consumption in a Mediterranean population using self-reported data and the biomarker gamma-glutamyl transferase (GGT); to examine the effects of alcohol (self-reported and biomarker-assessed) on epigenome-wide methylation; to analyze the association between alcohol (self-reported and biomarker-assessed) and telomere length and other aging biomarkers; and to explore the modulating effect of the Mediterranean diet (MedDiet). We performed blood epigenome-wide methylation studies (EWAS) in a Mediterranean cohort (aged 55-75 years). Self-reported alcohol consumption and MedDiet were assessed by questionnaires. A replication cohort (cohort 2) from the same area was also analyzed. For both cohorts, the DNA methylation-based biomarker (450-CpGs) was computed alongside epigenetic clocks for the following biological age acceleration metrics: DNAm telomere length, GrimAgeAcceleration, PhenoAgeAcceleration, and CausalityAgeYing (cohort 1). The association between the epigenomic biomarker and self-reported alcohol consumption was significant (p < 0.001) in both cohorts, but modest. However, the association was stronger when predicting high alcohol intake (AUC: 0.76; 95%CI: 0.65-0.86; p < 0.0001). In the EWAS, the hit (cg06690548-SLC7A11, in a cystine transporter that enhances glutathione production for antioxidant defense) was shared among the self-reported alcohol consumption, GGT, and the epigenomic biomarker, with alcohol linked to hypomethylation. We detected differential methylation in pre-selected oxidative stress-related genes. Enrichment analysis revealed "Rap1 signaling pathway" as the hit (p < 0.00001). High self-reported alcohol consumption and the epigenomic biomarker were associated with shorter telomere length (p < 0.05) in cohort 1. Additionally, a modulation by Mediterranean diet adherence was hypothesized. No significant associations were found between self-reported alcohol intake and the other aging biomarkers; however, the epigenomic score was directly associated with GrimAge, PhenoAge and CausAgeYing biomarkers in cohort 1 (p < 0.001), and two were replicated in cohort 2. In conclusion, alcohol intake has an impact on DNA methylation at the epigenome-wide level in this Mediterranean population, replicating the main hits from other populations and validating the epigenomic biomarker for intake, although improvement is needed. Moreover, several associations with aging biomarkers were observed.