[3 minute read]

DNA double helix

Results of a new analysis indicate that alcohol directly damages DNA, by shortening protective telomeres. 

Telomeres are repetitive DNA sequences that cap the end of chromosomes, protecting them from damage. Telomere length is considered a potential biological marker of ageing, since 50-100 base pairs are lost each time a cell replicates. Critically short telomeres prevent cell division, and can even trigger cell death. Based on studies using leucocytes (immune system cells), shorter telomere lengths have been associated with several ageing-related diseases including Alzheimer’s disease, cancer, and coronary artery disease. 

Telomere length is a partly heritable trait, but has also been found to be influenced by environmental and lifestyle factors, including exercise and smoking. However, to date the evidence from observational studies on how alcohol consumption impacts telomere length has been conflicting. One issue is that these studies used various different methods to measure telomere length and categorise alcohol intake. Furthermore, observational studies can be affected by confounding variables (factors other than the one being studied that are associated both with the disease and with the factor being studied) and reverse causation effects (where the outcome precedes and causes the exposure, instead of the other way around). 

To provide a more rigorous assessment, Oxford Population Health researchers led the first genetic study into the association between alcohol intake and telomere length, based on over 245,000 participants in the UK Biobank. The results have been published today in Molecular Psychiatry.

The research team used Mendelian Randomisation (MR), a method which estimates the association between genetically-predicted levels of an exposure and an outcome of interest. Leucocyte telomere length (LTL) measurements were quantified using DNA samples collected when participants were recruited to the UK Biobank. 

To estimate alcohol intake, the DNA samples were screened for 93 genetic variants that have previously been associated with weekly alcohol consumption, besides 24 variants that have previously been linked to a diagnosis of an alcohol use disorder. Because these genetic variants are randomly allocated and fixed before birth, MR studies are less likely to be affected by confounding factors or reverse causation than observational studies. 

To complement the MR analysis, the researchers also performed an observational assessment, based on the participants’ self-reported weekly alcohol intake at recruitment. 

Key findings 

  • Most of the participants were current drinkers, with only 3% being never drinkers and 4% being previous drinkers.
  • In the observational analysis, there was a significant association between high alcohol intake and shorter LTL. Compared with drinking less than 6 units of alcohol a week (about two large 250ml glasses of wine), drinking more than 29 units weekly (about ten glasses) was associated with between one and two years of age-related change on telomere length.
  • Individuals who had been diagnosed with an alcohol-use disorder had significantly shorter LTLs compared with controls, equivalent to between three and six years of age-related change.
  • Similarly, in the MR analysis, higher genetically-predicted alcohol consumption was associated with shorter telomere length. Each standard deviation increase in the genetically-predicted log-transformed weekly alcohol intake was associated with three years of ageing (for instance, an increase from 10 units of alcohol per week to 32.2 units).
  • However, the association between genetically-predicted alcohol consumption and telomere length was only significant for those drinking more than 17 units per week. This suggests that a minimum threshold of alcohol consumption may be required to damage telomeres.
  • The MR analysis also found a significant association between genetically-predicted alcohol-use disorder and telomere length, equivalent to around three years of ageing.

          Although these results do not conclusively prove that alcohol directly affects telomere length, two findings from the study support this being the case. 1) Effects were only found in current drinkers, and not previous or never-drinkers; 2) The most influential genetic variant in the MR analysis was AD1HB, an alcohol metabolism gene. 

          A potential biological mechanism to explain alcohol’s influence on telomere length is increased oxidative stress and inflammation. Ethanol metabolism can both produce reactive oxidative species that damage DNA and reduce levels of antioxidant compounds that protect against oxidative stress

          Study lead Dr Anya Topiwala said: ‘These findings support the suggestion that alcohol, particularly at excessive levels, directly affects telomere length. Shortened telomeres have been proposed as risk factors which may cause a number of severe age-related diseases, such as Alzheimer’s disease. Our results provide another piece of information for clinicians and patients seeking to reduce the harmful effects of excess alcohol. Furthermore, the dose of alcohol is important – even reducing drinking could have benefits.’