Alcohol use disorder is associated with DNA methylation-based shortening of telomere length and regulated by TESPA1: implications for aging

Abstract

Chronic heavy alcohol consumption is associated with increased mortality and morbidity and often leads to premature aging; however, the mechanisms of alcohol-associated cellular aging are not well understood. In this study, we used DNA methylation derived telomere length (DNAmTL) as a novel approach to investigate the role of alcohol use on the aging process. DNAmTL was estimated by 140 cytosine phosphate guanines (CpG) sites in 372 individuals with alcohol use disorder (AUD) and 243 healthy controls (HC) and assessed using various endophenotypes and clinical biomarkers. Validation in an independent sample of DNAmTL on alcohol consumption was performed (N = 4219). Exploratory genome-wide association studies (GWAS) on DNAmTL were also performed to identify genetic variants contributing to DNAmTL shortening. Top GWAS findings were analyzed using in-silico expression quantitative trait loci analyses and related to structural MRI hippocampus volumes of individuals with AUD. DNAmTL was 0.11-kilobases shorter per year in AUD compared to HC after adjustment for age, sex, race, and blood cell composition (p = 4.0 × 10−12). This association was partially attenuated but remained significant after additionally adjusting for BMI, and smoking status (0.06 kilobases shorter per year, p = 0.002). DNAmTL shortening was strongly associated with chronic heavy alcohol use (ps < 0.001), elevated gamma-glutamyl transferase (GGT), and aspartate aminotransferase (AST) (ps < 0.004). Comparison of DNAmTL with PCR-based methods of assessing TL revealed positive correlations (R = 0.3, p = 2.2 × 10−5), highlighting the accuracy of DNAmTL as a biomarker. The GWAS meta-analysis identified a single nucleotide polymorphism (SNP), rs4374022 and 18 imputed ones in Thymocyte Expressed, Positive Selection Associated 1(TESPA1), at the genome-wide level (p = 3.75 × 10−8). The allele C of rs4374022 was associated with DNAmTL shortening, lower hippocampus volume (p < 0.01), and decreased mRNA expression in hippocampus tissue (p = 0.04). Our study demonstrates DNAmTL-related aging acceleration in AUD and suggests a functional role for TESPA1 in regulating DNAmTL length, possibly via the immune system with subsequent biological effects on brain regions negatively affected by alcohol and implicated in aging.

Sex-difference in the association between social drinking, structural brain aging and cognitive function in older individuals free of cognitive impairment

“…However, recent studies report that alcohol-associated aging could be related to triggering neuroimmune responses, including pro-inflammatory cytokine release (107) which could affect telomere length. This was shown recently by Jung et al who reported that DNA methylation derived telomere length was 0.06 kilobases shorter per year in patients with alcohol use disorder compared to healthy controls after correcting for BMI and smoking status (p = 0.002) (108). The current study brings new insight by linking brain aging to cognitive performance which is critical for functionality and overall quality of life.…”

“…This was shown recently by Jung et al. who reported that DNA methylation derived telomere length was 0.06 kilobases shorter per year in patients with alcohol use disorder compared to healthy controls after correcting for BMI and smoking status (p = 0.002) ( 108 ). The current study brings new insight by linking brain aging to cognitive performance which is critical for functionality and overall quality of life.…”

Smoking and diabetes cause telomere shortening among alcohol use disorder patients

“…Similar to previous studies, telomere length was significantly shorter in alcohol use disorder patients than in healthy control subjects in this study 9 , 16 . Focusing on the factors that shorten telomeres, it has been reported that AUD patients with liver damage and higher γ-glutamyl transpeptidase (γ-GTP) and aspartate aminotransferase (AST) have shorter telomere lengths 17 , 18 . Thus, the direct effect of alcohol consumption on telomere length has been evaluated.…”

Genome-wide epistasis analysis reveals gene–gene interaction network on an intermediate endophenotype P-tau/Aβ42 ratio in ADNI cohort

“…TESPA1 is involved in the Ca 2+ transfer and genetic variation in TESPA1 might influence the aging process. Mounting evidence has shown that the accumulation of mitochondrial Ca 2+ is significantly related to neuronal apoptosis and other pathways, and enhanced neuronal apoptosis can lead to the neurodegeneration in AD 67 , 68 .…”