Epigenetic age acceleration in surviving versus deceased COVID-19 patients with acute respiratory distress syndrome following hospitalization

Abstract

Background Aging has been reported as a major risk factor for severe symptoms and higher mortality rates in COVID-19 patients. Molecular hallmarks such as epigenetic alterations and telomere attenuation reflect the biological process of aging. Epigenetic clocks have been shown to be valuable tools for measuring biological age in various tissues and samples. As such, these epigenetic clocks can determine accelerated biological aging and time-to-mortality across various tissues. Previous reports have shown accelerated biological aging and telomere attrition acceleration following SARS-CoV-2 infection. However, the effect of accelerated epigenetic aging on outcome (death/recovery) in COVID-19 patients with acute respiratory distress syndrome (ARDS) has not been well investigated. Results In this study, we measured DNA methylation age and telomere attrition in 87 severe COVID-19 cases with ARDS under mechanical ventilation. Furthermore, we compared dynamic changes in epigenetic aging across multiple time points until recovery or death. Epigenetic age was measured using the Horvath, Hannum, DNAm skin and blood, GrimAge, and PhenoAge clocks, whereas telomere length was calculated using the surrogate marker DNAmTL. Our analysis revealed significant accelerated epigenetic aging but no telomere attrition acceleration in severe COVID-19 cases. In addition, we observed epigenetic age deceleration at inclusion versus end of follow-up in recovered but not in deceased COVID-19 cases using certain clocks. When comparing dynamic changes in epigenetic age acceleration (EAA), we detected higher EAA using both the Horvath and PhenoAge clocks in deceased versus recovered patients. The DNAmTL measurements revealed telomere attrition acceleration in deceased COVID-19 patients between inclusion and end of follow-up and a significant change in dynamic telomere attrition acceleration when comparing patients who recovered versus those who died. Conclusions EAA and telomere attrition acceleration were associated with treatment outcomes in hospitalized COVID-19 patients with ARDS. A better understanding of the long-term effects of EAA in COVID-19 patients and how they might contribute to long COVID symptoms in recovered individuals is urgently needed.

The impact of COVID-19 on “biological aging”

“…A similar study by our group, using the same epigenetic clocks and surrogate telomere length estimator, observed a significant EAA measured via the Hannum, PhenoAge, and GrimAge clocks in COVID-19 patients with acute respiratory distress syndrome (ARDS). Our study also observed EAA across several phases of the disease ( 49 ). Additionally, comparing DNAmAge in COVID-19 patients who died to those who recovered at both baseline and final follow-up revealed EAA only in the GrimAge clock.…”

“…DNAmTL measurements revealed telomere attrition acceleration in deceased COVID-19 patients between inclusion and end of follow-up and a significant change in dynamic telomere attrition acceleration when comparing patients who recovered versus those who died ( 49 ). It was in line with another study where they showed that individuals with severe COVID-19 displayed significant DNAmTL attrition acceleration compared to individuals with non-severe COVID-19 ( 48 ).…”

“…The lack of reproducibility in these studies can be attributed to varying sample severity categorization and differences in comorbidities in the affected cohorts and controls. As there is no uniform standard to classify COVID-19, some studies define severity based on patient hospitalization, oxygen therapy, mechanical ventilation ( 26 , 47 , 48 , 51 , 52 ), or deceased status while other studies rely on the WHO clinical progression or Charlson severity index ( 47 , 49 ). In addition, data stratification between genders can affect the results obtained from the epigenetic clocks, since it was shown that males are at high risk for severe disease and mortality by COVID-19 ( 54 ).…”

“…Furthermore, the majority of epigenetic clocks exhibited variability and conflicting results across the different studies, however a notable consistency of increased bAge measured via the GrimAge clock was evident across numerous studies. This may be attributed to the fact that GrimAge was trained on factors closely related to the risk of respiratory diseases such as mortality and smoking, which may explain its effectiveness as an epigenetic marker for aging, particularly in the context of respiratory diseases ( 48 , 49 , 51 , 52 ).…”

Sex-Specific Associations between Prenatal Exposure to Di(2-ethylhexyl) Phthalate, Epigenetic Age Acceleration, and Susceptibility to Early Childhood Upper Respiratory Infections

“…For example, the Horvath pan-tissue clock [44] accurately estimates DNA methylation age across the lifespan in most human tissues. Epigenetic age acceleration (EAA) as estimated by the Horvath clock has been robustly associated with both early life exposures and later life morbidity and mortality [45], including respiratory illness outcomes [46]. EAA has also been consistently associated with, and even hailed as an emerging biomarker of asthma and atopic diseases in children [47,48] and may provide insight into the biological embedding of early life chemical exposures on immune system development.…”