Accelerated hippocampal biological aging in bipolar disorder

Abstract

Objectives Evidence suggests accelerated aging mechanisms in bipolar disorder (BD), including DNA methylation (DNAm) aging in blood. However, it is unknown whether such mechanisms are also evident in the brain, in particular in association with other biological clocks. To investigate this, we interrogated genome‐wide DNAm in postmortem hippocampus from 32 BD‐I patients and 32 non‐psychiatric controls group‐matched for age and sex from the NIMH Human Brain Collection Core. Methods DNAm age and epigenetic aging acceleration were estimated using the Horvath method. Telomere length (TL) and mitochondrial DNA (mtDNA) copy number were quantified by real‐time PCR. Between‐group differences were assessed by linear regression and univariate general linear models with age, sex, race, postmortem interval, tissue pH, smoking, and body mass index included as co‐variates. Results Groups did not differ for epigenetic aging acceleration when considering the entire sample. However, after splitting the sample by the median age, an epigenetic aging acceleration was detected in patients compared to controls among older subjects (P = .042). While TL did not differ between groups, a reduction in mtDNA copy number was observed in patients compared to controls (P = .047). In addition, significant correlations were observed between epigenetic aging acceleration and TL (r = −.337, P = .006), as well as between TL and mtDNA copy number (r = .274, P = .028). Conclusions Hippocampal aging may underlie neurocognitive dysfunctions observed in BD patients. Moreover, our results suggest a complex cross‐talk between biological clocks in hippocampus that may underlie clinical manifestations of premature aging in BD.

Neurobiology of bipolar disorders: a review of genetic components, signaling pathways, biochemical changes, and neuroimaging findings

“… 83 - 85 More recently, a marker of biological aging based solely on DNA methylation levels (“epigenetic age” or “DNA methylation age”) 86 has been used to explore the aging processes in BD, and the results suggest accelerated epigenetic aging in the blood and brain of BD patients compared to controls. 71 , 87 Recent evidence that the epigenetic clock can be pharmacologically reversed in humans 88 offers an interesting treatment possibility for the modulation of premature aging in BD.…”

Decreased DNA methylation at promoters and gene-specific neuronal hypermethylation in the prefrontal cortex of patients with bipolar disorder

“…In BD, several candidate-gene-based approaches have been performed, such as BDNF, COMT , and SLC6A4 genes in postmortem brains 12 . Additionally, comprehensive DNA methylation studies have revealed expression-linked DNA methylation changes in the cerebellum 14 , accelerated aging in the hippocampus 15 , loss of brain laterality associated with TGFB2 methylation 16 , and methylation imbalance of synaptic function-related genes between the frontal and temporal cortices 17 . However, there have been no established findings that were replicated in multiple studies.…”

The Role of Mitonuclear Incompatibility in Bipolar Disorder Susceptibility and Resilience Against Environmental Stressors

“…Several studies have found altered mtDNAcn in BD patients compared to controls. Significantly lower mtDNAcn have been observed in BD leukocytes (Chang et al, 2014;Yamaki et al, 2018;Wang et al, 2020), postmortem hippocampus (Fries et al, 2019), and left frontopolar cortex (Tsujii et al, 2019). Chung et al (2020) reported lower mtDNAcn in BDI patients compared to higher mtDNAcn in BDII patients compared to controls.…”