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.

Epigenetic age is accelerated in schizophrenia with age- and sex-specific effects and associated with polygenic disease risk

“…The difference between (predicted) DNAm and chronological age (Δage) is associated with a wide-range of health and disease outcomes. For example, DNAm age acceleration in blood is associated with all-cause mortality [15][16][17][18] , socioeconomic adversity and smoking 19 , metabolic outcomes, such as body mass index and obesity 20,21 , and brain-related phenotypes, such as Parkinson's disease, posttraumatic stress disorder, insomnia, major depressive disorder, and bipolar disorder [22][23][24]25,26 .…”

A review on shared clinical and biological aspects of bipolar disorder and frontotemporal dementia

“…Even in FTD cases with underlying monogenic causes, patients manifest symptoms only later in life (Chare et al, 2014). Biological evidence supports the theory of accelerating aging in BD (Fries et al, 2017;Vasconcelos-Moreno et al, 2017). This evidence includes the association between accelerated epigenetic aging and lower global functioning in BD patients (Fries et al, 2017).…”

Is bipolar disorder associated with premature aging?

“…Recently, Fries et al 17 demonstrated that it is possible to identify an acceleration of the epigenetic clock in individuals with BD compared to healthy controls. This epigenetic aging can be estimated by studying the methylation of different regions of DNA, which are known to change with age (DNA methylation age), and by the mitochondrial DNA copy number.…”

“…In that study, older patients with BD presented premature epigenetic aging compared to healthy controls, suggesting that epigenetic changes could be mechanistically linked to psychopathology in BD. 17 Another biological dimension of aging that seems to be altered in BD is the immune system aging. Several reports are available on the association between manic and depressive episodes and proinflammatory states, 18,19 Bipolar disorder (BD) is a chronic and recurrent and increased proportions of senescent T cells.…”