{"doi":"10.1016/j.ebiom.2021.103513","title":"Short telomeres and severe COVID-19: The connection conundrum","abstract":"The exponential rise of COVID-19 mortality among older adults has been rightly attributed to a declining immunity with age. Still, for unknown reasons, older adults are far more likely to die from COVID-19 than from the seasonal influenza, and this puzzle demands specific answers. One of them emerges from the telomere study by Wang et al [[1]Wang Q Codd V Raisi-Estabragh Z et al.Shorter leukocyte telomere length is associated with adverse COVID-19 outcomes: a cohort study in UK Biobank.EBioMedicine. 2021; 70103485Summary Full Text Full Text PDF Scopus (28) Google Scholar]. Other small studies [[2]Sanchez-Vazquez R Guío-Carrión A Zapatero-Gaviria A et al.Shorter telomere lengths in patients with severe COVID-19 disease.Aging (Albany NY). 2021; 13: 1-15Crossref PubMed Scopus (55) Google Scholar,[3]McGroder CF Zhang D Choudhury MA et al.Pulmonary fibrosis 4 months after COVID-19 is associated with severity of illness and blood leucocyte telomere length.Thorax. 2021; (thoraxjnl-2021-217031)Crossref PubMed Scopus (92) Google Scholar], each less than 100 participants, have also observed association of short hematopoietic cell telomeres with severe COVID-19. Wang's study, in contrast, consists of 6,775 adults with COVID-19. The study's importance, however, rests not in its size but in the fact that hematopoietic cell telomere length (TL) measurements had been performed years before the SARS-CoV-2 pandemic. This critical fact means that short hematopoietic cell TL, as expressed in leukocyte TL (LTL), preceded the onset of severe COVID-19– a conclusion that excludes reverse causality, namely, that SARS-CoV-2 infection shortens LTL. The TL variation within the individual's somatic cells is much smaller than the inter-individual TL variation. Accordingly, LTL has been used as a proxy for TL in leukocyte lineages and other somatic cells [[4]Aviv A Shay JW. Reflections on telomere dynamics and ageing-related diseases in humans.Philos Trans R Soc Lond B Biol Sci. 2018; 37320160436Crossref Scopus (108) Google Scholar]. That is relevant for another puzzling feature of COVID-19, i.e., the infection is often associated with lymphopenia [[5]Diao B Wang C Tan Y et al.Reduction and functional exhaustion of T cells in patients with Coronavirus disease.Front Immunol. 2020; 11: 827Crossref PubMed Scopus (1501) Google Scholar]. Transient lymphopenia is commonly observed in individuals with acute viral infections, but COVID-19 lymphopenia is atypical in its severity and long duration. This lymphopenia principally results from plummeting counts of T-cells, i.e., it is T-cell lymphopenia [[5]Diao B Wang C Tan Y et al.Reduction and functional exhaustion of T cells in patients with Coronavirus disease.Front Immunol. 2020; 11: 827Crossref PubMed Scopus (1501) Google Scholar,[6]Sette A Crotty S. Adaptive immunity to SARS-CoV-2 and COVID-19.Cell. 2021; 184: 861-880Summary Full Text Full Text PDF PubMed Scopus (940) Google Scholar]. The T-cell blood pool reflects a homeostatic balance between T cell depletion due to a host of factors and T-cell repletion, which is principally accomplished in adults through T-cell clonal expansion. Telomerase, the reverse transcriptase that elongates telomeres, is activated during T-cell clonal expansion and differentiation, but the activity of the enzyme is insufficient to counter telomere shortening with T-cell replication. T-cell replication is thus TL-dependent [[7]Patrick M Weng NP. Expression and regulation of telomerase in human T cell differentiation, activation, aging and diseases.Cell Immunol. 2019; 345103989Crossref PubMed Scopus (29) Google Scholar]. As hematopoietic cell TL shorten with age, T-cells from older adults have diminished clonal expansion capacity compared to young adults. For most healthy adults, such age-dependent T-cell TL shortening might not be a major problem in absence of an acute infection, because the long half-lives of ~ 5 years of naïve cells and ~ 5 months of memory T cells in the circulation","journal":"EBioMedicine","year":2021,"id":176567,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9517,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":226941,"name":"Abraham Aviv","orcid":"0000-0002-7441-0227","position":0,"is_corresponding":true}],"reference_count":9,"raw_metadata":null,"created_at":"2026-07-18T23:47:23.605867Z","pmid":"34333235","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}