Epigenetics of Delirium and Aging: Potential Role of DNA Methylation Change on Cytokine Genes in Glia and Blood Along With Aging

Abstract

Background: Delirium in elderly patients is common and dangerous. Major risk factors include aging and exogenous insults, such as infection or surgery. In animal models, aging enhances pro-inflammatory cytokine release from microglia in response to exogenous insults. The epigenetic mechanism DNA methylation (DNAm) regulates gene expression and changes with age. Older individuals may have methylation changes that influence the increased cytokine upon insult, but the degree to which aging affects DNAm of cytokine genes is not fully understood.Methods: The relationship between DNAm and aging of pro-inflammatory cytokine genes (TNF-alpha, IL1-beta, IL-6) was investigated using methylation array data in two cohorts. Brain and blood samples were collected from a neurosurgery cohort (NSG) of 21 subjects who underwent brain resection. A second cohort, the Grady Trauma Project (GTP), included blood samples from 265 subjects.Results: In the NSG cohort, a significant negative correlation between age and DNAm in brain was found at a CpG in IL-6. With the GTP dataset, significant negative correlations between age and DNAm were seen at most of the CpGs in TNF-alpha. Also, TNF-Alpha expression increases with age. These GTP DNAm correlations were also nominally significant in NSG blood samples. In neuronal negative NSG brain tissue, a similar negative trend was observed.Conclusions: With aging, a decrease in DNAm of cytokines gene CpGs in glia and blood was seen. As this can affect their expression, additional research is needed to fully elucidate the role of DNAm in aging and how it may influence the pathogenesis of delirium.

Alteration of the brain methylation landscape following postnatal inflammatory injury in rat pups

“…[74][75][76][77][78] Several world leaders in neonatal neurobiology, actively studying the inflammation-induced sensitization paradigm, are expressing grave concern over the increased risk of neurodegeneration following subsequent insults. 87 Furthermore, alteration of DNA methylation by adverse events can lead to discrepancy between chronological age and methylome age, which is associated to accelerated aging processes and age-related pathologies including neurodegenerative diseases and decreased white matter integrity. DNA methylation is a dynamic process that evolves with age and in pathological conditions.…”

Epigenetics biomarkers of delirium: immune response, inflammatory response and cholinergic synaptic involvement evidenced by genome-wide DNA methylation analysis of delirious inpatients

“…To fill this gap, we conducted the present study to compare DNAm status in blood from hospitalized patients with and without delirium to identify clinically useful epigenetic biomarkers for delirium from blood samples, which are routinely obtained from patients. We used blood for three reasons: 1) the function of monocytes in the blood is similar to that of microglia in that both release cytokines in response to exogenous stimulus, 2) our comparison of DNAm levels in live brain tissue (resected during neurosurgery) to those in blood from same individual collected at the same time point showed a high level of correlation genome-wide (13), and 3) our previous data showed a similar ageassociated decrease in DNAm in the pro-inflammatory cytokine gene TNF-alpha among glia and blood (12). To accomplish these goals, we conducted the present study investigating DNAm differences in blood between delirium patients and controls without delirium.…”

“…This data supports our hypothesis that in pro-inflammatory cytokine genes, DNAm levels decrease along with aging, and expression level increase. In addition, using a unique dataset from our own study comparing DNAm status from neurosurgically resected live human brains followed by fluorescence-activated cell sorting (FACS), we showed that DNAm of the TNF-alpha universally decreases with age among the glial (neuronal negative) component, but no such patterns were found among neurons (neuronal positive component) (12). This data also supports our hypothesis that the DNAm in proinflammatory genes decrease in glia along with aging, making microglia potentially more prone to express those cytokine genes and to have highghtend inflammatory response when exposed to external stimuli such as surgery or infection leading to delirium.…”

“…To support this hypothesis of DNAm change along with aging among pro-inflammatory cytokines, we previously reported that DNAm levels in blood decrease along with aging on the pro-inflammatory cytokine gene TNF-alpha, based on 265 participants from the Grady Trauma Project (GTP) (12). We also showed that expression level of TNF-alpha among the same subjects increased with aging (12). This data supports our hypothesis that in pro-inflammatory cytokine genes, DNAm levels decrease along with aging, and expression level increase.…”

“…Given the fact that aging and inflammation are the key risk factors of delirium, we focused on the fact that DNA methylation (DNAm) changes dynamically over the human lifespan and that epigenetic mechanisms control the expression of genes including those of cytokines. Thus, we hypothesized that epigenetic modifications specific to aging and delirium susceptibility occur in microglia; that similar modifications occur in blood; and that these epigenetic changes enhance reactions to exogenous insult, resulting in increased cytokine expression and delirium susceptibility (12). In fact, no published study has assessed DNAm and its relationship to delirium in humans, especially with genome-wide DNAm investigation.…”