Abstract
Harmful alcohol use is a leading cause of premature death and is associated with age-related disease. Biological ageing is highly variable between individuals and may deviate from chronological ageing, suggesting that biomarkers of biological ageing (derived from DNA methylation or brain structural measures) may be clinically relevant. Here, we investigated the relationships between alcohol phenotypes and both brain and DNA methylation age estimates. First, using data from UK Biobank and Generation Scotland, we tested the association between alcohol consumption (units/week) or hazardous use (Alcohol Use Disorders Identification Test [AUDIT] scores) and accelerated brain and epigenetic ageing in 20,258 and 8051 individuals, respectively. Second, we used Mendelian randomisation (MR) to test for a causal effect of alcohol consumption levels and alcohol use disorder (AUD) on biological ageing. Alcohol use showed a consistent positive association with higher predicted brain age (AUDIT-C: β =0.053, p=3.16 × 10-13 ; AUDIT-P: β =0.052, p=1.6 × 10-13 ; total AUDIT score: β =0.062, p=5.52 × 10-16 ; units/week: β =0.078, p=2.20 × 10-16 ), and two DNA methylation-based estimates of ageing, GrimAge (units/week: β =0.053, p=1.48 × 10-7 ) and PhenoAge (units/week: β =0.077, p=2.18x10-10 ). MR analyses revealed limited evidence for a causal effect of AUD on accelerated brain ageing (β =0.118, p=0.044). However, this result should be interpreted cautiously as the significant effect was driven by a single genetic variant. We found no evidence for a causal effect of alcohol consumption levels on accelerated biological ageing. Future studies investigating the mechanisms associating alcohol use with accelerated biological ageing are warranted.
Highlights
Harmful alcohol use is a leading cause for premature death globally.[1]
epigenetic age acceleration (EAA) was fit as the dependent variable, and alcohol consumption as the independent variable; sex, body mass index (BMI), smoking pack-years and inverse relationship matrix fitted as a random effect only for Set 1 in ASReml were added as covariates
We demonstrate a positive association between four measures of alcohol use and a metric of accelerated brain ageing, derived from structural magnetic resonance imaging (MRI)
Summary
Harmful alcohol use is a leading cause for premature death globally.[1]. Excessive alcohol use affects multiple tissues[2] and is associated with an increased risk for all-cause mortality[3] and age-related diseases including diabetes, liver diseases and dementia.[4]. Studies investigating associations between alcohol use and biological ageing have been limited to small sample sizes, report inconsistent findings and have not probed the potential causality of these associations Recent analytical approaches, such as that developed by Cole et al.,[6] use machine learning algorithms trained to predict chronological age from brain structural MRI data. The present study includes individuals who reported being current drinkers; extreme outliers (defined as participants with alcohol consumption in units/week >4* standard deviations [SD] from the mean) were excluded from the analysis. Adjusting DNAm PhenoAge for chronological age generated the measure of phenotypic epigenetic age acceleration, AgeAccelPheno
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