{"doi":"10.1152/physrev.00046.2021","title":"Telomere-mediated lung disease","abstract":"<jats:p> Parenchymal lung disease is the fourth leading cause of death in the United States; among the top causes, it continues on the rise. Telomeres and telomerase have historically been linked to cellular processes related to aging and cancer, but surprisingly, in the recent decade genetic discoveries have linked the most apparent manifestations of telomere and telomerase dysfunction in humans to the etiology of lung disease: both idiopathic pulmonary fibrosis (IPF) and emphysema. The short telomere defect is pervasive in a subset of IPF patients, and human IPF is the phenotype most intimately tied to germline defects in telomere maintenance. One-third of families with pulmonary fibrosis carry germline mutations in telomerase or other telomere maintenance genes, and one-half of patients with apparently sporadic IPF have short telomere length. Beyond explaining genetic susceptibility, short telomere length uncovers clinically relevant syndromic extrapulmonary disease, including a T-cell immunodeficiency and a propensity to myeloid malignancies. Recognition of this subset of patients who share a unifying molecular defect has provided a precision medicine paradigm wherein the telomere-mediated lung disease diagnosis provides more prognostic value than histopathology or multidisciplinary evaluation. Here, we critically evaluate this progress, emphasizing how the genetic findings put forth a new pathogenesis paradigm of age-related lung disease that links telomere abnormalities to alveolar stem senescence, remodeling, and defective gas exchange. </jats:p>","journal":"Physiological Reviews","year":2022,"id":610693,"datarank":0.7242470605953454,"base_score":4.8283137373023015,"endowment":4.8283137373023015,"self_citation_contribution":0.7242470605953454,"citation_network_contribution":0.0,"self_endowment_contribution":0.7242470605953454,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":124,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":264745,"name":"Mary Armanios","orcid":"0000-0002-7105-1847","position":1,"is_corresponding":false},{"id":58179,"name":"Jonathan K. Alder","orcid":"0000-0003-3741-6512","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Telomere-mediated lung disease","abstract":"<jats:p> Parenchymal lung disease is the fourth leading cause of death in the United States; among the top causes, it continues on the rise. Telomeres and telomerase have historically been linked to cellular processes related to aging and cancer, but surprisingly, in the recent decade genetic discoveries have linked the most apparent manifestations of telomere and telomerase dysfunction in humans to the etiology of lung disease: both idiopathic pulmonary fibrosis (IPF) and emphysema. The short telomere defect is pervasive in a subset of IPF patients, and human IPF is the phenotype most intimately tied to germline defects in telomere maintenance. One-third of families with pulmonary fibrosis carry germline mutations in telomerase or other telomere maintenance genes, and one-half of patients with apparently sporadic IPF have short telomere length. Beyond explaining genetic susceptibility, short telomere length uncovers clinically relevant syndromic extrapulmonary disease, including a T-cell immunodeficiency and a propensity to myeloid malignancies. Recognition of this subset of patients who share a unifying molecular defect has provided a precision medicine paradigm wherein the telomere-mediated lung disease diagnosis provides more prognostic value than histopathology or multidisciplinary evaluation. Here, we critically evaluate this progress, emphasizing how the genetic findings put forth a new pathogenesis paradigm of age-related lung disease that links telomere abnormalities to alveolar stem senescence, remodeling, and defective gas exchange. </jats:p>","is_dataset_classified":null,"base_score":4.8283137373023015,"endowment":4.8283137373023015,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"35532056","pmcid":"PMC9306791","openalex_id":"https://openalex.org/W4229363756","authors":[],"funders":[{"funder_name":"HHS | NIH | National Cancer Institute","grant_id":"CA225027","title":null},{"funder_name":"HHS | NIH | National Heart, Lung, and Blood Institute","grant_id":"HL119476","title":null},{"funder_name":"HHS | NIH | National Heart, Lung, and Blood Institute","grant_id":"HL135062","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA225027","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL135062","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL119476","title":null},{"funder_name":"National Institutes of Health","grant_id":"5R01HL119476-06","title":"Mechanisms of DNA damage induced emphysema"},{"funder_name":"National Institutes of Health","grant_id":"5R01HL135062-05","title":"Mechanisms of Telomere-Mediated Lung Disease"},{"funder_name":"National Institutes of Health","grant_id":"5R01CA225027-03","title":"Cancer Genetics of Short Telomere Syndromes"},{"funder_name":"S&amp;R Kuno Foundation","grant_id":"","title":null}],"total_grants":10,"fwci":11.4312,"citation_percentile":0.99216616,"influential_citations":0,"citation_trend":[{"year":2022,"count":5},{"year":2023,"count":24},{"year":2024,"count":37},{"year":2025,"count":38},{"year":2026,"count":20}],"oa_status":"hybrid","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1152/physrev.00046.2021","host_type":"journal"},{"url":"https://doi.org/10.1152/physrev.00046.2021","host_type":"publisher"},{"url":"https://journals.physiology.org/doi/pdf/10.1152/physrev.00046.2021","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/35532056","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9306791","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC9306791","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1152/physrev.00046.2021","host_type":""}],"fields_of_study":["Telomeres, Telomerase, and Senescence","Neonatal Respiratory Health Research","Occupational and environmental lung diseases","0301 basic medicine","03 medical and health sciences"],"mesh_terms":["Humans","Lung","Lung Diseases","Telomere","Telomerase","Idiopathic Pulmonary Fibrosis"],"keywords":["Telomere","Telomerase","Idiopathic pulmonary fibrosis","Pulmonary fibrosis","Lung cancer","Disease","Biology","Germline","Immunology","Medicine","Pathology","Lung","Fibrosis","Genetics","Internal medicine","Gene","Senescence","Emphysema","Stem Cells","Lung Diseases","Humans","Review"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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