(14) Epigenetic Clocks in Brain and Blood of Individuals with Substance Use Disorder

Introduction: A possible accelerated biological aging in patients with substance use disorders (SUD), i.e., an outpace of biological age over chronological age, is considered one of the main contributors to the adverse outcomes in SUD, such as premature mortality and an early onset of age-related diseases, i.e., cardiac, cerebrovascular, kidney, and liver diseases. So far, the evaluation of epigenetic clocks, which are accurate estimators of biological aging based on DNA methylation changes, has been limited to blood tissue in patients with SUD. Thus, the impact of epigenetic aging in the brain of individuals with SUD remains unknown.

Methods: Both postmortem brain (prefrontal cortex) and peripheral blood tissue from individuals with SUD (n=39), including alcohol (n=10), opioid (n=13), and stimulant use disorder (n=19), and non-psychiatric controls (n=10) were obtained from The University of Texas Health Science Center at Houston Brain Collection with Institutional Review Board approval. The DNA methylation profile of each sample was evaluated with Infinium Human Methylation EPIC BeadChip. DNA methylation values were used to calculate DNA methylation clocks -DNAmAge, DNAmAgeHannum, DNAmPhenoAge, DNAmGrimAge, and DNAmTL- and their respective measures of age acceleration with the Horvath’s DNA Methylation Age Calculator (https://dnamage.genetics.ucla.edu). First, we assessed differences in the epigenetic clocks between individuals with and without SUD in brain and blood tissues, separately using a linear regression model. Then, we evaluated possible cross-tissue differences on the evaluated epigenetic clocks in brain and blood samples from the same individuals using a linear regression model. Finally, we evaluated brain-blood correlations on epigenetic clocks to evaluate the use of blood measures as proxies of brain measures using either Pearson or Spearman tests according to the variable’s distribution.

Results: We found a higher DNAmPhenoAge (beta=0.203, p-value=0.006) and lower DNAmTL (beta=-0.180, p-value=0.03) in blood from individuals with SUD compared to controls. SUD subgroup analysis showed a lower brain DNAmTL in subjects with alcohol use disorder, compared to stimulant use disorder and controls (beta=0.02, p-value=0.02). Cross-tissue analyses indicated a lower blood DNAmTL and a higher blood DNAmGrimAge compared to their respective brain values in the SUD group. We found a positive correlation between brain and blood DNAmAge, DNAmAgeHannum, DNAmPhenoAge, DNAmGrimAge and DNAmAgeSkinBlood in the control group. In the SUD group, we did not find any significant correlation between brain and blood epigenetic variables.

Discussion: To the best of our knowledge, this is the first cross-tissue study investigating the relationship between brain and blood epigenetic age measures in postmortem tissues from individuals with SUD. The presence of positive and significant brain-blood correlations in controls indicate that peripheral measures of the epigenetic clocks might provide a good estimate of brain aging in subjects with no history of substance use disorders. Interestingly, for subjects with SUD, we found that blood-brain correlations depend on the specific type of drug used, which might suggest a tissue-specific effect of the particular substance being used.

Conclusion: This study highlights the relevance of tissue specificity in epigenetic aging studies, and suggests that peripheral measures of epigenetic clocks in SUD may depend on the specific type of drug used.

References: Horvath, S., & Raj, K. (2018). DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nature Reviews Genetics, 19(6), 371–384. doi: 10.1038/s41576-018-0004-3.
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Diversity, Equity, and Inclusion: Individuals were included in the present analysis regardless of their ancestry background. All the performed assessments included an ancestry principal components analysis to account for population stratification. In this way, our results are more likely to be applied to individuals with diverse ancestry background, benefiting a higher number of patients.