Accelerated epigenetic aging and mitochondrial DNA copy number in bipolar disorder

Abstract

Bipolar disorder (BD) has been previously associated with accelerated aging; yet, the mechanisms underlying this association are largely unknown. The epigenetic clock has been increasingly recognized as a valuable aging marker, although its association with other biological clocks in BD patients and high-risk subjects, such as telomere length and mitochondrial DNA (mtDNA) copy number, has never been investigated. We included 22 patients with BD I, 16 siblings of BD patients, and 20 healthy controls in this analysis. DNA was isolated from peripheral blood and interrogated for genome-wide DNA methylation, mtDNA copy number, and telomere length. DNA methylation age (DNAm age) and accelerated aging were calculated using the Horvath age estimation algorithm in blood and in postmortem brain from BD patients and nonpsychiatric controls using publicly available data. Older BD patients presented significantly accelerated epigenetic aging compared to controls, whereas no difference was detected among the younger subjects. Patients showed higher levels of mtDNA copy number, while no difference was found between controls and siblings. mtDNA significantly correlated with epigenetic age acceleration among older subjects, as well and with global functioning in our sample. Telomere length did not show significant differences between groups, nor did it correlate with epigenetic aging or mtDNA copy number. These results suggest that BD may involve an accelerated epigenetic aging, which might represent a novel target for treating BD and subjects at risk. In particular, our results suggest a complex interplay between biological clocks to determine the accelerated aging and its consequences in BD.

Fig. 1

Scatterplot illustrating the significant and positive correlation between DNA methylation age (DNAm age in years, calculated based on the Horvath algorithm) and chronological age (years). Analysis was performed by Pearson correlation coefficient

Fig. 2. Epigenetic age acceleration and mitochondrial DNA (mtDNA) copy number in patients with bipolar disorder and siblings

Bars (panels a and b) represent mean + standard error of the mean. Epigenetic age acceleration was calculated by regressing the predicted DNA methylation (DNAm) age to the chronological age of the subjects. Negative and positive values represent younger and older DNAm ages compared to their chronological ages, respectively. Panels c and d represent median ± 95% confidence interval of mtDNA copy number in each group. Panels a, c, and e represent the analyses performed with the whole sample, while panels b, d, and f represent only the older subjects ( > 33 years). a Between-group comparison of epigenetic age acceleration in the entire samples (n = 58). b Between-group comparison of epigenetic age acceleration in subjects older than 33 years old. c mtDNA copy number in the entire sample. d mtDNA copy number in subjects older than 33 years old. e Correlation between epigenetic age acceleration and mtDNA copy number in the entire sample. f Correlation between epigenetic age acceleration and mtDNA copy number in subjects older than 33 years old

Fig. 3

Telomere length in patients with BD, siblings, and healthy controls. The results are displayed as median ± 95% confidence interval. No significant differences were detected between groups (p > 0.05)