Novel biomarkers identified in otherwise healthy older adults with asymptomatic seropositive cytomegalovirus (CMV) infection may reflect epigenetic age acceleration and immune dysregulation, according to study findings published in The Journal of infectious Diseases.

Chronic viral infections can cause accelerated epigenetic aging, which can be observed through epigenetic changes. The quantity of methylated DNA in the human genome, in correlation with chronologic age, is used to measure epigenetic age. Epigenetic age acceleration is measured by calculating the difference between observed and predicted epigenetic age, and it has the potential to be used as a clinical marker for disease progression.

Although the serologic prevalence of CMV infection increases with chronologic age and is associated with inflammatory-mediated diseases in older populations, the subclinical effects of CMV infection in otherwise healthy older adults is not well understood. To address this knowledge gap, a team of investigators in Canada conducted a study to determine the impact  CMV infection has on epigenetic age and immune dysregulation. The investigators used DNA methylation assays to determine epigenetic age and T-cell immunophenotyping to determine immune dysregulation.

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A total of 87 participants aged 61 years and older were included in the study; 65 were seropositive for CMV infection and 22 were seronegative for CMV infection. Participants with CMV infection had significantly increased lymphocyte counts compared with participants without CMV infection (P =.0112). Participants with seropositive CMV infection had decreased CD4/CD8 T-cell ratios compared with participants without CMV infection (P =.0084). The investigators also found that participants without CMV infection were less likely to have a very low T-cell ratio (<1) compared with participants with CMV infection (4.6% vs 16.9%, respectively).

Although both groups did not have significant differences in percentage or absolute numbers of CD4 T cells, the participants who were seropositive for CMV infection had a significantly increased percentage (P =.0034) of and absolute number (P =.0021) of CD8 T cells.  The participants who were seropositive for CMV infection also had a significant increase in CD28- T cells.

Epigenetic age was calculated for each participant, and CMV serostatus was blinded; however, due to technical difficulties, 14 samples were not sequenced. Of the remaining samples, it was found that participants with CMV infection had a significantly increased epigenetic age compared with those without infection (65.34 years vs 59.53 years, respectively; P =.0016). Computational analysis showed an epigenetic age acceleration of 5.1 years among participants with CMV infection (P =.0116).

“[W]e highlight the need to explore CMV vaccinations and prophylaxis with antiviral drugs, such as letermovir and valganciclovir, which have both been shown to reduce CMV infection and CD8 [T-cell] activation in the case of the latter,” the investigators noted.

“Further studies are needed to determine these proposed interventions with respect to their potential clinical significance and effect on [epigenetic age],” they concluded.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Poloni C, Szyf M, Cheishvili D, Tsoukas CM. Are the healthy vulnerable? Cytomegalovirus seropositivity in healthy adults is associated with accelerated epigenetic age and immune-dysregulation. J Infect Dis. Published online July 13, 2021. doi:10.1093/infdis/jiab365