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January 29, 2023
EXECUTIVE SUMMARY
Oxford Population Health researchers have found that alcohol directly accelerates aging by damaging DNA in telomeres.
- The research used a genetic approach (Mendelian Randomisation) to investigate the effects of alcohol on aging, along with an observational assessment based on self-reported weekly alcohol intake.
- Results showed a significant association between high alcohol intake and shorter telomere length, equivalent to 1–2 years of age-related change.
- The MR analysis found a significant association between higher genetically-predicted alcohol consumption and shorter telomere length, equivalent to 3 years of aging, …
- … and a significant association between genetically-predicted alcohol-use disorder and telomere length, equivalent to 3 years of aging.
- A potential mechanism for alcohol’s influence on telomere length is increased oxidative stress and inflammation.
- Shortened telomeres have been proposed as risk factors which may cause a number of severe age-related diseases, such as Alzheimer’s disease
SOURCE:
Technology Networks
July 27, 2022
Traditionally, investigating this has been challenging due to the lack of reliable methods to measure biological aging.
In addition, it was not clear from observational studies whether alcohol was the true cause of any effect, or if it was linked to other factors, such as socio-economic status.
Researchers from Oxford Population Health have published results from a new genetic-based analysis which suggest that alcohol directly accelerates aging by damaging DNA in telomeres. The findings are published in Molecular Psychiatry.
alcohol directly accelerates aging by damaging DNA in telomeres.
Telomeres are repetitive DNA sequences that cap the end of chromosomes, protecting them from damage.
Telomere length is considered an indicator of biological aging, since 50–100 DNA bases are lost each time a cell replicates.
Once telomeres become too short, cells can no longer divide and may even die.
Previous studies have linked shorter telomere lengths with several aging-related diseases including Alzheimer’s disease, cancer, and coronary artery disease.
Previous studies have linked shorter telomere lengths with several aging-related diseases including Alzheimer’s disease, cancer, and coronary artery disease.
In this analysis, the researchers investigated the association between alcohol intake and telomere length in over 245,000 participants in the UK Biobank.
They used a genetic approach called Mendelian Randomisation (MR), the first time this has been applied to investigate the effects of alcohol on aging.
This method uses ‘genetic proxies’ to predict the level of exposure for each participant.
For this study, the researchers used genetic variants that have previously been associated with alcohol consumption and alcohol use disorders in large-scale genome-wide association studies.
To complement the MR analysis, the researchers also performed an observational assessment, based on the participants’ self-reported weekly alcohol intake at recruitment.
In the observational analysis, there was a significant association between high alcohol intake and shorter telomere length.
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 250ml glasses of 14% alcohol by volume wine) was associated with between one and two years of age-related change on telomere length.
… drinking more than 29 units weekly (about ten 250ml glasses of 14% alcohol by volume wine) 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 telomere lengths compared with controls, equivalent to between 3 and 6 years of age-related change.
Similarly, in the MR analysis, higher genetically-predicted alcohol consumption was associated with shorter telomere length.
An increase from 10 units to 32 units per week was associated with the equivalent of 3 years of aging.
Individuals who had been diagnosed with an alcohol-use disorder had significantly shorter telomere lengths compared with controls, equivalent to between 3 and 6 years of age-related change.
An increase from 10 units to 32 units per week was associated with the equivalent of 3 years of aging.
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 amount of alcohol consumption may be required to damage telomeres.
This suggests that a minimum amount 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 3 years of aging.
Most of the participants were current drinkers, with only 3% being never drinkers and 4% being previous drinkers. 51% were men, 49% were women, and the average age was 57 years.
Study lead, Dr Anya Topiwala from Oxford Population Health, 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.’
Shortened telomeres have been proposed as risk factors which may cause a number of severe age-related diseases, such as Alzheimer’s disease.
For both the observational and MR analysis, telomere lengths were measured using leucocytes (immune system cells) from the participants’ DNA samples collected when participants were first recruited to the UK Biobank.
In the MR analysis, alcohol intake was estimated by screening DNA samples 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, the results give greater confidence that alcohol directly affects telomere length, rather than a different factor being responsible.
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.
According to the research team, a potential biological mechanism to explain alcohol’s influence on telomere length is increased oxidative stress and inflammation.
The process which breaks down ethanol in the body can both produce reactive oxidative species that damage DNA and reduce levels of antioxidant compounds that protect against oxidative stress.
Dr Richard Piper, Chief Executive of Alcohol Change UK, said:
‘We welcome all research into the effects of alcohol on the human body. This particular study shows clear links between consuming alcohol and ageing, and points towards a possible link between alcohol and Alzheimer’s.
The researchers are transparent that this study does not prove a causal link, but they also make a well-argued case about the likely biological mechanism.
In general, there is an ever-larger body of science showing how, exactly, alcohol causes so much ill-health and so many early deaths.’
Reference:
Topiwala A, Taschler B, Ebmeier KP, et al. Alcohol consumption and telomere length: Mendelian randomization clarifies alcohol’s effects. Mol. Psych. 2022. doi: 10.1038/s41380–022–01690–9.
This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.
Originally published at https://www.technologynetworks.com.
ORIGINAL PUBLICATION
Alcohol consumption and telomere length: Mendelian randomization clarifies alcohol’s effects [excerpt version]
Molecular Psichiatry
A. Topiwala 1✉, B. Taschler 2 , K. P. Ebmeier 3 , S. Smith2 , H. Zhou 4,5, D. F. Levey 4,5, V. Codd6,7, N. J. Samani6,7, J. Gelernter 4,5, T. E. Nichols 1,2 and S. Burgess 8,9
Abstract
- Alcohol’s impact on telomere length, a proposed marker of biological aging, is unclear.
- We performed the largest observational study to date (in n = 245,354 UK Biobank participants) and compared findings with Mendelian randomization (MR) estimates.
- Two-sample MR used data from 472,174 participants in a recent genome-wide association study (GWAS) of telomere length. Genetic variants were selected on the basis of associations with alcohol consumption (n = 941,280) and alcohol use disorder (AUD) (n = 57,564 cases).
- Non-linear MR employed UK Biobank individual data. MR analyses suggested a causal relationship between alcohol traits, more strongly for AUD, and telomere length.
- Higher genetically-predicted AUD (inverse variance-weighted (IVW) β = −0.06, 95% confidence interval (CI): −0.10 to −0.02, p = 0.001) was associated with shorter telomere length.
- There was a weaker association with genetically-predicted alcoholic drinks weekly (IVW β = −0.07, CI: −0.14 to −0.01, p = 0.03).
- Results were consistent across methods and independent from smoking.
- Non-linear analyses indicated a potential threshold relationship between alcohol and telomere length.
- Our findings indicate that alcohol consumption may shorten telomere length.
- There are implications for age-related diseases.
Our findings indicate that alcohol consumption may shorten telomere length.
There are implications for age-related diseases.
Introduction
Telomere length is considered a potential biological marker of aging [1]. These repetitive nucleotide sequences, together with associated protein complexes, form a ‘cap’ at the ends of chromosomes, protecting them from damage. As a cell’s replicative machinery cannot completely copy the ends of chromosomes, 50–100 base pairs are lost at each division. Telomere attrition therefore occurs with increasing cellular age. Critically short telomeres trigger cell death or replicative senescence, or occasionally continued division, mutation and genetic aberrations. Epidemiologically, shorter leucocyte telomere length (LTL) has been linked to several aging-related diseases including Alzheimer’s disease, cancer and coronary artery disease [2, 3]. Telomere length is partly heritable and linked to sex [4], ethnicity and paternal age [5], but has also been linked to environmental and lifestyle factors, including exercise [6], smoking [7] and alcohol consumption [8].
Observational studies of the relationship between alcohol use and telomere length have produced conflicting results. The largest such study to date, of 4567 individuals, found no association between alcohol intake and either baseline or longitudinal change in telomere length [9]. Another analysis of two American cohorts (n = 2623) also reported null findings [10]. On the other hand, a few small studies (sample size range: 255–1800) have observed associations with heavy drinking or AUD. Participants with AUD have been reported to have shorter telomeres compared to healthy controls [11]. A longitudinal study of Helsinki businessmen observed that higher midlife alcohol consumption was associated with shorter telomere length in older age [8]. Drinking >30 g/day of alcohol in older participants was associated with shorter telomeres in a Korean study [12]. Associations were stronger in those experiencing the alcohol flush reaction, raising the intriguing possibility that acetaldehyde, ethanol’s toxic breakdown product, is mechanistically involved. In a recent review of 27 studies, 10 showed significant associations between alcohol use and telomere length [13]. The studies included cross-sectional and longitudinal designs. The majority comprised European participants with ages ranging from the third to seventh decade. Most studies observed positive associations between alcohol and LTL. However heterogeneity between studies in methods of quantifying telomere length and categorizing alcohol intake hindered meta-analysis and aggregation of the data.
MR seeks to identify potentially causal determinants of an outcome. It estimates the association between genetically predicted levels of an exposure and an outcome of interest. Residual confounding and reverse causation aim to be less of a concern than in most other methods of analyzing observational data [14]. With MR, genetic proxies can be used to study the effects of genetically-predicted variability in alcohol consumption or AUD risk. To our knowledge, no MR study of alcohol and telomere length has yet been attempted.
We conducted a large observational study of two alcohol phenotypes, alcohol consumption and AUD, and leucocyte. We then performed linear MR analyses to investigate the evidence for a causal effect between alcohol consumption/AUD and LTL. Estimates generated by our observational and genetic methods were compared. Genetic distinction between different alcohol use traits motivates their separate analysis. Quantity/frequency measures such as drinks per week and AUDIT-C (Alcohol Use Disorders Identification Test Consumption, a 3 item screening tool), while moderately genetically correlated with AUD, have distinct patterns of genetic correlation with other traits [13]. Furthermore, as there has been much speculation about potential J-shaped relationships between alcohol and health outcomes [15], we performed a non-linear MR analysis to examine the shape of the relationship between alcohol consumption and telomere length. Multiple robust methods were employed to test MR assumptions. These included use of non-drinkers as negative controls, testing one of the key assumptions that genetic proxies only impact an outcome via the exposure. Given the widespread exposure to alcohol across the world, clarification of any potential causal impact on telomere length is important.
Methods, Results and Other Sections
See the original publication (this is an excerpt version only)
Key findings
Using observational and MR approaches we observed consistent associations between two alcohol phenotypes, alcohol consumption and AUD, and shorter telomere length. Non-linear analyses were suggestive of a threshold relationship between alcohol intake and telomere length.
Discussion of findings
Estimates for associations between genetically-predicted alcohol consumption and telomere length were broadly consistent across the four MR methods employed. Whilst IV assumptions can never be tested empirically for each SNP, each method allows for different violations of the MR assumptions. Therefore consistent results across methods give greater confidence about the plausibility of the assumptions. The strongest association between genetically predicted alcohol consumption/AUD and telomere length was for rs1229984. The finding is biologically plausible, as this SNP is within an alcohol metabolism gene, ADH1B. It could result from greater power to detect a causal effect, as rs1229984 had the strongest associations with a broad range of alcohol use traits of any instrument used. The evidence in support of a causal effect of alcohol consumption on telomere length was weaker than that for AUD, given the relatively large p value (0.03), and the shift in estimate when the most influential SNP (rs1229984) was removed from the analysis.
Again, for AUD all MR methods gave consistent causal estimates. Alcohol consumption and alcohol use disorder are distinct phenotypes, with only partial overlap in their genetic associations. The reasons for this are unclear [28]. But unlike the quantity-frequency measure AUDIT-C, AUD shows strong genetic correlation with a range of psychiatric disorders and negative medical outcomes [29]. AUD heritability could be partially explained by inherited personality traits, such as impulsivity [30] or sensation-seeking [31] which are less relevant for lower intakes. Overlap with genetic risk to psychiatric disorders such as depression [32] could also be a factor, or even propensity to physiological side effects following large quantities of alcohol.
To contextualize the effect size, in the observational analysis, drinking >29 units (>232 g ethanol, ~ten 250 ml glasses of 14% alcohol by volume (ABV) wine) of alcohol weekly compared to <6 units (~ two 250 ml glass of wine) was equivalent to 1–2 years of age-related change on telomere length. The MR effect sizes were greater − 1 SD higher genetically-predicted log-transformed alcoholic drinks weekly was equivalent to 3 years of aging. Possible explanations for greater associations in MR analyses are that these may capture the cumulative effects of lifetime propensity to drinking, and be subject to less confounding than observational estimates.
Significant associations between genetically-predicted alcohol and telomere length were only found in current drinkers, providing support that the only path from the genetic variants to LTL is through alcohol. Furthermore, the strength of evidence for a causal effect of alcohol on telomere length was greater in heavier drinkers. This finding suggests a threshold effect, in that a necessary minimum amount of alcohol consumption is required to damage telomeres. Similar relationships with alcohol have been described for other health outcomes [33]. Additionally, multivariable MR analysis suggested that alcohol’s effects are direct and not mediated or confounded by smoking or physical activity.
We are unable to temporally pinpoint alcohol’s impact on LTL, especially as both alcohol consumption and LTL are heritable [19, 30]. We hypothesize three (not mutually exclusive) potential pathways: (1) direct effects of adult alcohol consumption on adult LTL, (2) parental alcohol consumption preconception influencing gamete and therefore inherited LTL, (3) maternal alcohol consumption leading to LTL shortening in utero. One mechanism by which alcohol could exert an influence on telomere length could be via oxidative stress and inflammation. Oxidative stress has been demonstrated, in vitro and in vivo, to affect telomere length [34]. Ethanol metabolism can produce reactive oxygen species and reactive nitrogen species [35, 36]. In addition, ethanol can reduce levels of critical cellular antioxidants, such as glutathione [37, 38], compounding the oxidative stress.
Strengths
Strengths of this study include the triangulation of observational and MR approaches. The observational analysis is the largest to date. No previous MR analysis has been undertaken. Two alcohol traits, alcohol consumption and AUD were examined. Univariable and multivariable two-sample MR analyses were performed, as well as individual-level data interrogated in a non-linear MR analysis. Genetic associations were extracted from the largest GWAS available for both exposures and outcomes published. Multiple sensitivity analyses, including use of negative controls and multivariable MR were undertaken to explore the robustness of the findings.
Limitations
Some limitations need to be acknowledged. Genetic variants explained a low variance of alcohol traits. Despite this, our analysis had 85% statistical power to detect a 0.08 standard deviation change in telomere length for a 1 standard deviation increase in alcohol consumption. Due to size differences between groups, we had greater power to detect genetic associations in current drinkers compared to never drinkers. Estimates were similar when excluding related individuals, although less precise and no longer attained nominal statistical significance in quintile 5 in the nonlinear analyses. The observational analysis, use of negative controls, and non-linear MR analysis used self-report to determine alcohol intake. Although this is the only feasible method at scale, it may be subject to misclassification bias. MR estimates the causal effect of lifetime exposure to alcohol. Hence estimates do not necessarily equate to effect sizes if alcohol intake were modified following an intervention during adult life. Genetic associations with alcohol and telomere length were calculated in those with European ancestry and therefore may not apply to other populations with different ancestry groups. Two sample MR assumes that the two populations are broadly similar. UK Biobank is likely subject to a healthy volunteer bias. Prevalence of alcohol dependence in UKB was much lower than general population estimates [38]. This likely reflects cases being defined on the basis of ICD codes in linked health records, which would capture only the most severe cases. MR techniques rely on a number of assumptions which we have tried to test where possible, but residual uncertainty inevitably remains. Finally, telomere length was measured in leucocytes, but the extent to which this reflects other organ tissues is not clear [39].
Conclusions
In conclusion, associations between alcohol traits, and genetically-predicted alcohol traits, and telomere length were found.
Non-linear analyses suggested that a threshold alcohol intake might be necessary to impact telomere length.
These findings lend support to alcohol, particularly at dependent levels, being a causal determinant of telomere length.
Multiple sensitivity analyses to assess assumptions of the estimation methods offer a degree of confidence to their plausibility.
These findings provide another piece of information in the arsenal of clinicians seeking to persuade patients of the harmful effects of alcohol.
Shortened telomeres are proposed as causal risk factors for a number of age-related diseases like Alzheimer’s disease.
Furthermore, the dose of alcohol is important –even reducing drinking could have benefits.
References
See the original publication
About the authors & affiliations
A. Topiwala 1✉, B. Taschler 2 , K. P. Ebmeier 3 , S. Smith2 , H. Zhou 4,5, D. F. Levey 4,5, V. Codd6,7, N. J. Samani6,7, J. Gelernter 4,5, T. E. Nichols 1,2 and S. Burgess 8,9
Nuffield Department Population Health, Big Data Institute, University of Oxford, Oxford OX3 7LF, UK. 2 Wellcome Centre for Integrative Neuroimaging (WIN FMRIB), Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK. 3 Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK. 4 Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. 5 Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA. 6 Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. 7 NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK. 8 MRC Biostatistics Unit, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SR, UK. 9 Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge CB1 8RN, UK
