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. 2025 Feb 4;23(1):60.
doi: 10.1186/s12916-025-03881-x.

Exploring DNA methylation, telomere length, mitochondrial DNA, and immune function in patients with Long-COVID

Andrea Polli  1   2   3 , Lode Godderis  4   5 , Dries S Martens  6 , Madhura Shekhar Patil  4 , Jolien Hendrix  4   7   8 , Arne Wyns  7 , Jente Van Campenhout  7 , Emma Richter  4 , Lara Fanning  4 , Olivia Vandekerckhove  9 , Eveline Claeys  9 , Wim Janssens  9   10 , Natalie Lorent  9   10
Affiliations

Exploring DNA methylation, telomere length, mitochondrial DNA, and immune function in patients with Long-COVID

Andrea Polli et al. BMC Med. .

Abstract

Background: Long-COVID is defined as the persistency or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation. Common persistent symptoms are fatigue, sleep disturbances, post-exertional malaise (PEM), pain, and cognitive problems. Long-COVID is estimated to be present in about 65 million people. We aimed to explore clinical and biological factors that might contribute to Long-COVID.

Methods: Prospective longitudinal cohort study including patients infected with SARS-CoV-2 between March 2020 and March 2022. Patients were assessed between 4 and 12 months after infection at the COVID follow-up clinic at UZ Leuven. We performed a comprehensive clinical assessment (including questionnaires and the 6-min walking test) and biological measures (global DNA methylation, telomere length, mitochondrial DNA copy number, inflammatory cytokines, and serological markers such as C-reactive protein, D-dimer, troponin T).

Results: Of the 358 participants, 328 were hospitalised, of which 130 had severe symptoms requiring intensive care admission; 30 patients were ambulatory referrals. Based on their clinical presentation, we could identify 6 main clusters. One-hundred and twenty-seven patients (35.4%) belonged to at least one cluster. The bigger cluster included PEM, fatigue, sleep disturbances, and pain (n = 57). Troponin T and telomere shortening were the two main markers predicting Long-COVID and PEM-fatigue symptoms.

Conclusions: Long-COVID is not just one entity. Different clinical presentations can be identified. Cardiac involvement (as measured by troponin T levels) and telomere shortening might be a relevant risk factor for developing PEM-fatigue symptoms and deserve further exploring.

Keywords: Immune system; Long-COVID; PACS; Post-acute COVID-19 syndrome; Telomere length.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study was performed according to the Declaration of Helsinki and approved by the institutional ethics committees of KU/UZ Leuven (S64081 and amendment S65411). All participants agreed to participate and signed a written informed consent form. Consent for publication: No image, video, or other details of any participant are reported in the manuscript. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Flowchart summarising patients’ flow and the cohort used for the analyses
Fig. 2
Fig. 2
Between-group differences for troponin T HS (A), telomere length (B), and mtDNAcn (C). Values are expressed as unstandardised predicted values; as predicted from the general linear model (including age and BMI as covariates, gender and ICU as fixed factors). Troponin T is expressed in ng/mL. Telomere length and mtDNAcn are calculated as the ratio between telomere sequence (T) and mtDNA sequence and the single copy gene (S), resulting in the T/S or mtDNA/S ratio, respectively
See this image and copyright information in PMC

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