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Is Cellular Senescence a Biological Feature of Long COVID? A Transcriptomic Analysis Across Comparative Postacute Sequelae Phenotypes

Year: 2026
Type: article
Abstract: BACKGROUND: Cellular senescence, involving cell-cycle arrest and inflammatory factor release, may play a role in Long COVID development. We investigated the role of senescence-associated genes across multiple postacute sequelae phenotypes. METHODS: Participants from a cohort study were grouped into post-COVID-19 groups: (1) sensory, fatigue/difficulty thinking, and difficulty breathing/exercise intolerance, identified through a machine learning analysis of symptom data; (2) cognitive impairment, measured using a screening cognitive assessment tool (BRACE); and (3) persistent dyspnea, identified using a symptom-scale known to correlate with a 6-minute-walk-test. Postinfection whole-blood samples underwent transcriptomic analysis with 47 125 genes used as the reference signature for gene set enrichment analysis against the SenMayo cellular-senescence query gene set (n = 125); enrichment were based on normalized enrichment scores (NES). RESULTS: SenMayo genes were significantly upregulated in the early postinfection period in (1) 56 individuals who subsequently developed Long COVID symptom phenotypes, compared to 104 who did not develop Long COVID symptoms (NES = 6.04, P = .001); (2) 32 individuals with long-term cognitive impairment compared with 40 without long-term cognitive impairment measured by BRACE (NES = 2.58, P = .032); and (3) 26 participants who had persistent dyspnea compared with 53 without persistent dyspnea measured by the validated dyspnea instrument (NES = 6.29, P = .001). ETS2 was upregulated across all impairment-related phenotypes, while other SenMayo genes showed phenotype-specific variability. CONCLUSIONS: This study suggests a role of senescence-associated genes in the development of Long COVID, including shared and unique transcriptomic patterns across phenotypes.
DOI: 10.1093/infdis/jiag315
Authors: Nusrat J Epsi, Stephanie A Richard, Michael J Morris, David A Lindholm, Anuradha Ganesan, Rhonda E Colombo, Katrin Mende, Milissa U Jones, Allison M W Malloy, Leah H Rubin, Brian K Agan, David R Tribble, Timothy H Burgess, Clifton Dalgard, Michael A Puskarich, Simon D Pollett
Institutions: Henry M. Jackson Foundation, Uniformed Services University of the Health Sciences, Brooke Army Medical Center, Joint Base San Antonio, Walter Reed National Military Medical Center, Madigan Army Medical Center, Johns Hopkins University, University of Minnesota
Language: English
Field: Medicine
Open Access status: hybrid
Estimated APC paid: $4,763
Funders: U.S. Department of Defense, Henry M. Jackson Foundation, National Institutes of Health, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, National Institute of Allergy and Infectious Diseases, Madigan Army Medical Center
Awards: G1113378013, G1286242323, G1381013786, G2693322613, G3637497573, DATA CENTER FOR EPIDEMIOLOGIC INVESTIGATIONS OF HIV
OpenAlex ID: W7165787750
FWCI: 3.369
Cites: 47
Cited by: 1
Related to: 10