Decelerated epigenetic aging associated with mood stabilizers in the blood of patients with bipolar disorder

Abstract

There is high mortality among patients with bipolar disorder (BD). Studies have reported accelerated biological aging in patients with BD. Recently, Horvath and Hannum et al. independently developed DNA methylation (DNAm) profiles as “epigenetic clocks,” which are the most accurate biological age estimate. This led to the development of two accomplished measures of epigenetic age acceleration (EAA) using blood samples, namely, intrinsic and extrinsic EAA (IEAA and EEAA, respectively). IEAA, which is based on Horvath’s clock, is independent of blood cell counts and indicates cell-intrinsic aging. On the other hand, EEAA, which is based on Hannum’s clock, is associated with age-dependent changes in blood cell counts and indicates immune system aging. Further, Lu et al. developed the “GrimAge” clock, which can strongly predict the mortality risk, and DNAm-based telomere length (DNAmTL). We used a DNAm dataset from whole blood samples obtained from 30 patients with BD and 30 healthy controls. We investigated Horvath EAA, IEAA, Hannum EAA, EEAA, Grim EAA, DNAmTL, and DNAm-based blood cell composition. Compared with controls, there was a decrease in Horvath EAA and IEAA in patients with BD. Further, there was a significant decrease in Horvath EAA and IEAA in patients with BD taking medication combinations of mood stabilizers (including lithium carbonate, sodium valproate, and carbamazepine) than in those taking no medication/monotherapy. This study provides novel evidence indicating decelerated epigenetic aging associated with mood stabilizers in patients with BD.

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

“…Despite the simple cell culture model, these overlapping DMRs and opposite directions of changes between the postmortem brain and cell culture imply the pathophysiological importance of these DMRs. A similar opposite direction of DNA methylation changes related to mood stabilizers has been reported not only in a gene-specific manner 26 but also in systematic alterations in accelerated aging in BD 70 . Although the precise molecular mechanism remains unclear, mood stabilizers can normalize epigenetic regulation in brain cells 12 , leading to the amelioration of multiple DMRs between BD patients and controls.…”

“GrimAge,” an epigenetic predictor of mortality, is accelerated in major depressive disorder

“…However, many questions remain unanswered. Our data do not inform on the stability vs. reversibility of these changes 40 , 41 , on the actual association of these epigenetic changes with later illness and mortality in MDD, on whether any causal relationships exist between MDD and GrimAge, or on whether the GrimAge differences we noted are specific to MDD among other psychiatric illnesses. Furthermore, while our goal was to assess the possibility of accelerated GrimAging in MDD rather than identify its causes, the ultimate aim of this line of research is to identify the biological mechanisms linking MDD to diminished lifespan and “healthspan” 14 , 15 .…”

“GrimAge,” an epigenetic predictor of mortality, is accelerated in Major Depressive Disorder

“…However, many questions remain unanswered. Our data do not inform on the stability vs. reversibility of these changes(40,41), on the actual association of these epigenetic changes with later illness and mortality in MDD, on whether any causal relationships exist between MDD and GrimAge, or on whether the GrimAge differences we noted are specific to MDD among other psychiatric illnesses. Furthermore, while our goal was to assess the possibility of accelerated GrimAging in MDD rather than identify its causes, the ultimate aim of this line of research is to identify the biological mechanisms linking MDD to diminished lifespan and “healthspan”(14,15).…”