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Initially described as a disease primarily affecting young women, it now increasingly affects the elderly. Age-related pathomechanisms of PAH remain, however, unclear. In a translational approach combining preclinical disease models and analyses of human cohorts, we probed for a role of the anti-ageing protein Klotho, which acts as a co-receptor for fibroblast growth factor 23 (FGF23) in the pathogenesis of PAH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Mice aged 114\u2013117 weeks showed moderate spontaneous PAH with right ventricular (RV) hypertrophy and dysfunction relative to young mice aged &amp;lt; 40 weeks. This effect was further pronounced upon hypoxic exposure (10% O2) for 14 days. Histological sections showed pulmonary vascular wall thickening of small pulmonary arterioles. Similar findings were obtained in mice with a partial Klotho deficiency (kl\/+) that developed RV systolic pressures (RVSP) of 72.58 \u00b1 3.3\u2005mmHg within two weeks of hypoxia. Aged mice and kl\/+ mice had elevated plasma levels of FGF23, further amplified by hypoxic exposure. ELISA-based measurements in serum of patients from a cross-sectional study with PAH aged 60 years or older confirmed an increase in circulatory FGF23. Immunohistochemistry staining of lung tissue showed increased proliferative activity of PASMC in kl\/+ mice, and recombinant FGF23 elevated proliferative activity of PASMC in vitro. The hyperproliferative response to FGF23 was prevented by siRNA-mediated knockdown of fibroblast growth factor receptor 1 in PASMC. In kl\/+ mice, FGF23 neutralisation using an anti-FGF23 antibody reduced RVSP, improved RV dysfunction and RV hypertrophy and prevented pulmonary vascular remodelling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings identify the accumulation of FGF23 as novel mechanism of pulmonary vascular remodeling in PAH. Targeting dysregulated Klotho\/FGF23 signalling may present a promising therapeutic strategy in elderly patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvag048","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T12:45:07Z","timestamp":1772023507000},"page":"764-777","source":"Crossref","is-referenced-by-count":0,"title":["Dysregulated Klotho and FGF23 signalling aggravates vascular remodelling in age-related pulmonary hypertension"],"prefix":"10.1093","volume":"122","author":[{"given":"Paul-Lennard","family":"Perret","sequence":"first","affiliation":[{"name":"Charite\u0301-Universita\u0308tsmedizin Berlin, corporate Member of Freie Universita\u0308t Berlin and Humboldt-Universita\u0308t zu Berlin , Charite\u0301platz 1, Berlin 10117 ,","place":["Germany"]},{"name":"Institute of Physiology, Charite\u0301 University Medicine Berlin, corporate Member of Freie University Berlin and Humboldt-University Charite\u0301platz 1 , Berlin 10117 ,","place":["Germany"]},{"name":"DZHK: German Center for Cardiovascular Research, partner Site Berlin, Berlin ,","place":["Germany"]},{"name":"Berlin Institute of Health (BIH) , Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan H","family":"Kim","sequence":"additional","affiliation":[{"name":"Charite\u0301-Universita\u0308tsmedizin Berlin, corporate Member of Freie Universita\u0308t Berlin and Humboldt-Universita\u0308t zu Berlin , Charite\u0301platz 1, Berlin 10117 ,","place":["Germany"]},{"name":"Institute of Physiology, Charite\u0301 University Medicine Berlin, corporate Member of Freie University Berlin and Humboldt-University Charite\u0301platz 1 , Berlin 10117 ,","place":["Germany"]},{"name":"DZHK: German Center for Cardiovascular Research, partner Site Berlin, Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annika","family":"Winkler","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charite\u0301 (DHZC) , Augustenburger Platz 1, Berlin 13353 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christiane","family":"Ott","sequence":"additional","affiliation":[{"name":"DZHK: German Center for Cardiovascular Research, partner Site Berlin, Berlin ,","place":["Germany"]},{"name":"Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbr\u00fccke , Nutethal 14558 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Willem","family":"Bintig","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology, Charit\u00e9-Universit\u00e4tsmedizin Berlin , Charit\u00e9platz 1, Berlin 10117 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa C","family":"Funk-Hilsdorf","sequence":"additional","affiliation":[{"name":"Charite\u0301-Universita\u0308tsmedizin Berlin, corporate Member of Freie Universita\u0308t Berlin and Humboldt-Universita\u0308t zu Berlin , Charite\u0301platz 1, Berlin 10117 ,","place":["Germany"]},{"name":"Institute of Physiology, Charite\u0301 University Medicine Berlin, corporate Member of Freie University Berlin and Humboldt-University Charite\u0301platz 1 , Berlin 10117 ,","place":["Germany"]},{"name":"DZHK: German Center for Cardiovascular Research, partner Site Berlin, Berlin ,","place":["Germany"]},{"name":"Berlin Institute of Health (BIH) , Berlin ,","place":["Germany"]},{"name":"Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charite\u0301 (DHZC) , Augustenburger Platz 1, Berlin 13353 ,","place":["Germany"]},{"name":"Deutsches Herzzentrum der Charit\u00e9\u2014Medical Heart Center of Charit\u00e9 and German Heart Institute Berlin, Department of Cardiology, Angiology and Intensive Care, Campus Charit\u00e9 Mitte, Charit\u00e9-Universit\u00e4tsmedizin Berlin , Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik","family":"Asmus","sequence":"additional","affiliation":[{"name":"Charite\u0301-Universita\u0308tsmedizin Berlin, corporate Member of Freie Universita\u0308t Berlin and Humboldt-Universita\u0308t zu Berlin , Charite\u0301platz 1, Berlin 10117 ,","place":["Germany"]},{"name":"Institute of Physiology, Charite\u0301 University Medicine Berlin, corporate Member of Freie University Berlin and Humboldt-University Charite\u0301platz 1 , Berlin 10117 ,","place":["Germany"]},{"name":"DZHK: German Center for Cardiovascular Research, partner Site Berlin, Berlin ,","place":["Germany"]},{"name":"Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charite\u0301 (DHZC) , Augustenburger Platz 1, Berlin 13353 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Szandor","family":"Simmons","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Charite\u0301 University Medicine Berlin, corporate Member of Freie University Berlin and Humboldt-University Charite\u0301platz 1 , Berlin 10117 ,","place":["Germany"]},{"name":"DZHK: German Center for Cardiovascular Research, partner Site Berlin, Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Michalick","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Charite\u0301 University Medicine Berlin, corporate Member of Freie University Berlin and Humboldt-University Charite\u0301platz 1 , Berlin 10117 ,","place":["Germany"]},{"name":"DZHK: German Center for Cardiovascular Research, partner Site Berlin, Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip D","family":"Solymosi","sequence":"additional","affiliation":[{"name":"Charite\u0301-Universita\u0308tsmedizin Berlin, corporate Member of Freie Universita\u0308t Berlin and Humboldt-Universita\u0308t zu Berlin , Charite\u0301platz 1, Berlin 10117 ,","place":["Germany"]},{"name":"Institute of Physiology, Charite\u0301 University Medicine Berlin, corporate Member of Freie University Berlin and Humboldt-University Charite\u0301platz 1 , Berlin 10117 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Knaus","sequence":"additional","affiliation":[{"name":"Institute for Chemistry and Biochemistry, Freie Universit\u00e4t Berlin , Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catrin","family":"Herpich","sequence":"additional","affiliation":[{"name":"Department of Geriatrics and Medical Gerontology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin , Berlin ,","place":["Germany"]},{"name":"Department of Nutrition and Gerontology, German Institute for Human Nutrition Potsdam-Rehbr\u00fccke , Nuthetal 14558 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristina","family":"Norman","sequence":"additional","affiliation":[{"name":"Department of Geriatrics and Medical Gerontology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin , Berlin ,","place":["Germany"]},{"name":"Department of Nutrition and Gerontology, German Institute for Human Nutrition Potsdam-Rehbr\u00fccke , Nuthetal 14558 ,","place":["Germany"]},{"name":"Institute of Nutritional Science, University of Potsdam , Nuthetal 14558 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ursula","family":"M\u00fcller-Werdan","sequence":"additional","affiliation":[{"name":"Department of Geriatrics and Medical Gerontology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin , Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vasile","family":"Foris","sequence":"additional","affiliation":[{"name":"Division of Pulmonology, Department of Internal Medicine, Medical University of Graz , Graz ,","place":["Austria"]},{"name":"Ludwig Boltzmann Institute for Lung Vascular Research , Graz ,","place":["Austria"]},{"name":"Channing Division of Network Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School , Boston, MA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabor","family":"Kovacs","sequence":"additional","affiliation":[{"name":"Division of Pulmonology, Department of Internal Medicine, Medical University of Graz , Graz ,","place":["Austria"]},{"name":"Ludwig Boltzmann Institute for Lung Vascular Research , Graz ,","place":["Austria"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makoto","family":"Kuro-O","sequence":"additional","affiliation":[{"name":"Division of Anti-Aging Medicine, Center for Molecular Medicine, Jichi Medical University , Shimotsuke ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tilman","family":"Grune","sequence":"additional","affiliation":[{"name":"DZHK: German Center for Cardiovascular Research, partner Site Berlin, Berlin ,","place":["Germany"]},{"name":"Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbr\u00fccke , Nutethal 14558 ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jakob","family":"Voelkl","sequence":"additional","affiliation":[{"name":"DZHK: German Center for Cardiovascular Research, partner Site Berlin, Berlin ,","place":["Germany"]},{"name":"Institute for Physiology and Pathophysiology, Johannes Kepler University Linz , Linz ,","place":["Austria"]},{"name":"Department of Nephrology and Medical Intensive Care, Charit\u00e9-Universit\u00e4tsmedizin Berlin , Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6209-7416","authenticated-orcid":false,"given":"Jana","family":"Grune","sequence":"additional","affiliation":[{"name":"Charite\u0301-Universita\u0308tsmedizin Berlin, corporate Member of Freie Universita\u0308t Berlin and Humboldt-Universita\u0308t zu Berlin , Charite\u0301platz 1, Berlin 10117 ,","place":["Germany"]},{"name":"Institute of Physiology, Charite\u0301 University Medicine Berlin, corporate Member of Freie University Berlin and Humboldt-University Charite\u0301platz 1 , Berlin 10117 ,","place":["Germany"]},{"name":"DZHK: German Center for Cardiovascular Research, partner Site Berlin, Berlin ,","place":["Germany"]},{"name":"Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charite\u0301 (DHZC) , Augustenburger Platz 1, Berlin 13353 ,","place":["Germany"]},{"name":"DZL: German Center for Lung Research, Partner Site Berlin, Berlin ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang M","family":"Kuebler","sequence":"additional","affiliation":[{"name":"Charite\u0301-Universita\u0308tsmedizin Berlin, corporate Member of Freie Universita\u0308t Berlin and Humboldt-Universita\u0308t zu Berlin , Charite\u0301platz 1, Berlin 10117 ,","place":["Germany"]},{"name":"Institute of Physiology, Charite\u0301 University Medicine Berlin, corporate Member of Freie University Berlin and Humboldt-University Charite\u0301platz 1 , Berlin 10117 ,","place":["Germany"]},{"name":"DZHK: German Center for Cardiovascular Research, partner Site Berlin, Berlin ,","place":["Germany"]},{"name":"DZL: German Center for Lung Research, Partner Site Berlin, Berlin ,","place":["Germany"]},{"name":"Keenan Research Centre, St. Michael\u2019s Hospital , Toronto, ON ,","place":["Canada"]},{"name":"Department of Physiology, University of Toronto , Toronto, ON ,","place":["Canada"]},{"name":"Department of Surgery, University of Toronto , Toronto, ON ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,2,27]]},"reference":[{"key":"2026042812512097000_cvag048-B1","doi-asserted-by":"crossref","first-page":"2200879","DOI":"10.1183\/13993003.00879-2022","article-title":"2022 ESC\/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension","volume":"61","author":"Humbert","year":"2023","journal-title":"Eur Respir J"},{"key":"2026042812512097000_cvag048-B2","doi-asserted-by":"crossref","first-page":"j5492","DOI":"10.1136\/bmj.j5492","article-title":"Pulmonary arterial hypertension: pathogenesis and clinical 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