{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T01:31:11Z","timestamp":1789608671794,"version":"build-2803163510"},"reference-count":24,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100009647","name":"Ministry of Health","doi-asserted-by":"publisher","award":["MOH\u2010000319"],"award-info":[{"award-number":["MOH\u2010000319"]}],"id":[{"id":"10.13039\/100009647","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006510","name":"Duke University","doi-asserted-by":"publisher","award":["Duke\/Duke\u2010NUS\/RECA(Pilot)\/2022\/0060"],"award-info":[{"award-number":["Duke\/Duke\u2010NUS\/RECA(Pilot)\/2022\/0060"]}],"id":[{"id":"10.13039\/100006510","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010890","name":"Chinese Government Scholarship","doi-asserted-by":"publisher","award":["202307720074"],"award-info":[{"award-number":["202307720074"]}],"id":[{"id":"10.13039\/501100010890","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Metabolic dysfunction\u2010associated steatotic liver disease (MASLD) is primarily driven by a Western\u2010style diet and exacerbated with aging, yet underlying mechanisms remain unclear. Given the essential role of thyroid hormone (TH) in MASLD progression, we hypothesized that impaired intrahepatic TH action during aging promotes MASLD progression and severity of MASH with fibrosis. We evaluated hepatic TH metabolism in young (18\u201324\u2009weeks) and old (108\u2013120\u2009weeks) C57BL\/6J mice fed either a normal chow diet (NCD) or a Western diet with fructose (WDF) for 8\u2009weeks. Liver histology, metabolic parameters, inflammatory and fibrotic markers, intrahepatic thyroxine (T4) and triiodothyronine (T3) concentrations, and activities of deiodinase enzymes (Dio1 and Dio3) were measured. Additionally, an in\u00a0vitro hepatocyte senescence model using AML12 cells was employed to assess age\u2010related alterations in deiodinase expression and the therapeutic efficacy of resmetirom (an FDA\u2010approved thyromimetic). Aging and WDF synergistically exacerbated hepatic inflammation and fibrosis, accompanied by significant reductions in intrahepatic T4 and T3. Aging markedly decreased Dio1 activity, which converts T4 to active T3, whereas WDF partially restored Dio1 in old mice. Conversely, Dio3 activity, responsible for TH inactivation, increased with age but exhibited age\u2010dependent differential responses to WDF, findings mirrored in senescent hepatocytes. Notably, resmetirom significantly reduced senescence markers, inhibited senescence\u2010associated secretory phenotype (SASP) genes, inflammasome activation, endoplasmic reticulum (ER) stress, and activated autophagy. Collectively, our findings demonstrate that aging and stress by a Western\u2010style diet synergistically impair hepatic TH signaling, accelerating MASLD progression. Furthermore, resmetirom improved hepatic senescence, highlighting its potential therapeutic repurposing for aging\u2010associated hepatic pathologies, including MASLD.<\/jats:p>","DOI":"10.1111\/acel.70600","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T09:39:23Z","timestamp":1782207563000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Aging and Western Diet Synergistically Impair Hepatic Thyroid Hormone Signaling to Promote Metabolic Dysfunction\u2010Associated Steatotic Liver Disease (\n                    <scp>MASLD<\/scp>\n                    ) in Mice"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5534-9005","authenticated-orcid":false,"given":"Xinru","family":"Zhang","sequence":"first","affiliation":[{"name":"Endocrine Laboratory, Department of Laboratory Medicine, Amsterdam Gastroenterology, Amsterdam UMC University of Amsterdam  Amsterdam the Netherlands"},{"name":"Research Institute Amsterdam Gastroenterology Endocrinology &amp; Metabolism (AGEM), Amsterdam UMC  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhulika","family":"Tripathi","sequence":"additional","affiliation":[{"name":"Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program Duke\u2013NUS Medical School  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun Ting","family":"Goh","sequence":"additional","affiliation":[{"name":"Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program Duke\u2013NUS Medical School  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chee Seng","family":"Chan","sequence":"additional","affiliation":[{"name":"Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program Duke\u2013NUS Medical School  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Boelen","sequence":"additional","affiliation":[{"name":"Endocrine Laboratory, Department of Laboratory Medicine, Amsterdam Gastroenterology, Amsterdam UMC University of Amsterdam  Amsterdam the Netherlands"},{"name":"Research Institute Amsterdam Gastroenterology Endocrinology &amp; Metabolism (AGEM), Amsterdam UMC  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Yen","sequence":"additional","affiliation":[{"name":"Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program Duke\u2013NUS Medical School  Singapore Singapore"},{"name":"National Heart Centre Singapore  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brijesh Kumar","family":"Singh","sequence":"additional","affiliation":[{"name":"Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program Duke\u2013NUS Medical School  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6466-8497","authenticated-orcid":false,"given":"Eveline","family":"Bruinstroop","sequence":"additional","affiliation":[{"name":"Research Institute Amsterdam Gastroenterology Endocrinology &amp; Metabolism (AGEM), Amsterdam UMC  Amsterdam the Netherlands"},{"name":"Department of Endocrinology and Metabolism Amsterdam UMC, University of Amsterdam  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2012.10.031"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2014\u20101302"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018\u201000475"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1530\/etj\u201022\u20100211"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2021.101266"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201057616\u2010w"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29466"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.101083"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140\u20106736(19)32517\u20106"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2309000"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v30.i7.652"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232213714"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010023\u201002602\u20102"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1413853"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13530"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.00276"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2024.10.018"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.103740"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575\u2010024\u201000991\u20104"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2020.100064"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005\u20100872"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci44678"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.102031"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.3350\/cmh.2024.0431"}],"container-title":["Aging 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