COVID-19 Measurably Accelerates Epigenetic Aging Over Three Years

Biological aging is not determined solely by the calendar—DNA methylation patterns, which can be read by epigenetic clocks, capture the cumulative effects of lifestyle, environment, and disease on the pace of aging. COVID-19 was hypothesized to accelerate this process, but long-term longitudinal evidence in community-dwelling adults remained scarce before this study.

Researchers at the Hungarian University of Sport Science enrolled 54 volunteers (35 female, 19 male; mostly middle-aged to older adults) whose blood was collected in late 2019, just before the pandemic began. Follow-up samples were collected approximately three years later in late 2022 to early 2023. Of the 54 participants, 27 self-reported having had COVID-19 at some point during the intervening period. Physical fitness measures—VO₂ max, grip strength, and vertical jump—were also assessed at both time points. Eight validated epigenetic clocks were applied to whole-blood DNA methylation data obtained via the Illumina EPIC array.

Across the full cohort, the picture from epigenetic clocks was mixed: DNAmAge showed accelerated aging over the three years, while five clocks (DNAmAgeSkinBlood, DNAmAgeHannum, DNAmFitAge, PhenoAge, and DNAmTL) indicated slowed aging—likely reflecting differences in what biological processes each clock captures. Critically, when infected and non-infected groups were compared after adjusting for baseline age, BMI, sex, and fitness variables, COVID-19 infection was associated with significantly greater epigenetic age acceleration on DNAmGrimAge (p=0.024), DNAmGrimAge2 (p=0.047), and DNAmFitAge (p=0.032). GrimAge clocks are particularly notable because they are strongly predictive of mortality and morbidity. Female participants showed a stronger DNAmAge acceleration effect and also displayed slowed aging on SkinBloodClock and DNAmTL, suggesting sex-specific epigenetic responses to COVID-19.

At the individual CpG site level, the most significant methylation decrease occurred in the promoter region of H1FNT, a gene encoding a testis-specific histone important for spermatogenesis, while the promoter of CSTL1 (encoding Cystatin-like 1, involved in immune regulation) showed the greatest increase. These findings suggest COVID-19 may leave epigenetic marks on genes beyond those directly involved in immune response.

The authors conclude that COVID-19 exerts a mild but measurable long-term effect on epigenetic aging, consistent with prior shorter-term studies showing post-infection increases in PhenoAge and GrimAge. Importantly, the 3-year longitudinal design distinguishes this study from cross-sectional work and allows detection of sustained, rather than transient, epigenetic effects. Nonetheless, the modest sample size, self-reported infection status without PCR confirmation, absence of data on COVID-19 severity or vaccination, and inability to control for all lifestyle changes during the pandemic limit definitive conclusions.