Biological aging markers in blood and brain tissue indicate age acceleration in alcohol use disorder

Lea Zillich; Metin Cetin; Elisabeth M Hummel; Eric Poisel; Gabriel R Fries; Josef Frank; Fabian Streit; Jerome C Foo; Lea Sirignano; Marion M Friske; Bernd Lenz; Sabine Hoffmann; Kristina Adorjan; Falk Kiefer; Georgy Bakalkin; Anita C Hansson; Falk W Lohoff; Olli Kärkkäinen; Eloise Kok; Pekka J Karhunen; Greg T Sutherland; Consuelo Walss-Bass; Rainer Spanagel; Marcella Rietschel; Dirk A Moser; Stephanie H Witt

doi:10.1111/acer.15241

Biological aging markers in blood and brain tissue indicate age acceleration in alcohol use disorder

Alcohol Clin Exp Res (Hoboken). 2024 Feb;48(2):250-259. doi: 10.1111/acer.15241. Epub 2024 Jan 26.

Authors

Lea Zillich^{1

2}, Metin Cetin¹, Elisabeth M Hummel³, Eric Poisel¹, Gabriel R Fries⁴, Josef Frank¹, Fabian Streit¹, Jerome C Foo¹, Lea Sirignano¹, Marion M Friske⁵, Bernd Lenz⁶, Sabine Hoffmann⁶, Kristina Adorjan^{7

8}, Falk Kiefer⁶, Georgy Bakalkin⁹, Anita C Hansson⁵, Falk W Lohoff², Olli Kärkkäinen¹⁰, Eloise Kok^{11

12

13}, Pekka J Karhunen^{13

14}, Greg T Sutherland¹⁵, Consuelo Walss-Bass⁴, Rainer Spanagel⁵, Marcella Rietschel¹, Dirk A Moser³, Stephanie H Witt^{1

16}

Affiliations

¹ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
² Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
³ Department of Genetic Psychology, Faculty of Psychology, Ruhr Universität Bochum, Bochum, Germany.
⁴ Louis A. Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.
⁵ Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁶ Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁷ Department of Psychiatry and Psychotherapy, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany.
⁸ Institute of Psychiatric Phenomics and Genomics, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany.
⁹ Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
¹⁰ School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
¹¹ Department of Pathology, University of Helsinki, Helsinki, Finland.
¹² HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland.
¹³ Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
¹⁴ Fimlab Laboratories Ltd., Pirkanmaa Hospital District, and Finnish Cardiovascular Research Centre Tampere, Tampere, Finland.
¹⁵ Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
¹⁶ Center for Innovative Psychiatric and Psychotherapeutic Research, Biobank, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

PMID: 38276909
PMCID: PMC10922212 (available on 2025-02-01)
DOI: 10.1111/acer.15241

Abstract

Background: Alcohol use disorder (AUD) is associated with increased mortality and morbidity risk. A reason for this could be accelerated biological aging, which is strongly influenced by disease processes such as inflammation. As recent studies of AUD show changes in DNA methylation and gene expression in neuroinflammation-related pathways in the brain, biological aging represents a potentially important construct for understanding the adverse effects of substance use disorders. Epigenetic clocks have shown accelerated aging in blood samples from individuals with AUD. However, no systematic evaluation of biological age measures in AUD across different tissues and brain regions has been undertaken.

Methods: As markers of biological aging (BioAge markers), we assessed Levine's and Horvath's epigenetic clocks, DNA methylation telomere length (DNAmTL), telomere length (TL), and mitochondrial DNA copy number (mtDNAcn) in postmortem brain samples from Brodmann Area 9 (BA9), caudate nucleus, and ventral striatum (N = 63-94), and in whole blood samples (N = 179) of individuals with and without AUD. To evaluate the association between AUD status and BioAge markers, we performed linear regression analyses while adjusting for covariates.

Results: The majority of BioAge markers were significantly associated with chronological age in all samples. Levine's epigenetic clock and DNAmTL were indicative of accelerated biological aging in AUD in BA9 and whole blood samples, while Horvath's showed the opposite effect in BA9. No significant association of AUD with TL and mtDNAcn was detected. Measured TL and DNAmTL showed only small correlations in blood and none in brain.

Conclusions: The present study is the first to simultaneously investigate epigenetic clocks, telomere length, and mtDNAcn in postmortem brain and whole blood samples in individuals with AUD. We found evidence for accelerated biological aging in AUD in blood and brain, as measured by Levine's epigenetic clock, and DNAmTL. Additional studies of different tissues from the same individuals are needed to draw valid conclusions about the congruence of biological aging in blood and brain.

Keywords: alcohol use disorder; biological aging; copy numbers of mitochondrial DNA; epigenetic clocks; telomere length.

Abstract

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