{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T19:46:06Z","timestamp":1792611966412,"version":"4.5.0"},"reference-count":52,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFA0805100"],"award-info":[{"award-number":["2021YFA0805100"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82370866"],"award-info":[{"award-number":["82370866"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Aging drives physiological decline and predisposes individuals to multiple age\u2010related pathologies, constituting a major global health challenge. Growth hormone receptor (GHR), a critical regulator of growth, development, and metabolism, has emerged as a potential therapeutic target. However, its precise role in aging and age\u2010related diseases remains incompletely defined. Here, we demonstrate that hepatocyte\u2010specific GHR knockout mice display accelerated aging\u2010related phenotypes, characterized by shortened lifespan, enhanced cellular senescence, reduced metabolic stress resilience, cognitive decline, impaired bone mineralization, and exacerbated inflammaging. Elevated circulating GH following hepatocyte\u2010specific GHR ablation mediates adipose\u2010liver crosstalk that promotes adipose lipolysis and CD36\u2010dependent hepatic steatosis. Hepatocyte\u2010specific GHR deficiency also promotes liver aging and aggravates age\u2010related hepatic pathologies in both naturally aged and high\u2010fat diet (HFD)\u2010fed mice. Mechanistically, loss of hepatic GHR impairs STAT5b phosphorylation while upregulating PPAR\u03b3 expression. Enhanced nuclear translocation of PPAR\u03b3 activates transcription of\n                    <jats:italic>Pdk4<\/jats:italic>\n                    and\n                    <jats:italic>Cd36<\/jats:italic>\n                    , leading to mitochondrial damage and ectopic lipid accumulation. Together, dysregulated lipid metabolism and mitochondrial dysfunction establish a self\u2010amplifying vicious cycle that accelerates aging and its pathophysiology. Pharmacological inhibition of PDK4 in\u00a0vivo effectively ameliorates the age\u2010related pathologies induced by hepatocyte\u2010specific GHR ablation. These findings identify hepatic GHR signaling as an important contributor to age\u2010related hepatic pathology and a candidate node within the broader network of factors driving systemic aging phenotypes, highlighting hepatocyte GHR signaling as a promising therapeutic target for age\u2010related liver disorders.\n                  <\/jats:p>","DOI":"10.1111\/acel.70741","type":"journal-article","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T04:25:59Z","timestamp":1790396759000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatocyte Growth Hormone Receptor Ablation Is Associated With Aging Phenotypes and Hepatic Mitochondrial Dysfunction"],"prefix":"10.1111","volume":"25","author":[{"given":"Kangkang","family":"Yang","sequence":"first","affiliation":[{"name":"Liaoning Provence Key Lab of Genome Engineered Animal Models, Institute of Genome Engineered Animal Models for Human Diseases, National Center of Genetically Engineered Animal Models for International Research Dalian Medical University  Dalian Liaoning P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuli","family":"Jian","sequence":"additional","affiliation":[{"name":"Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences Dalian Medical University  Dalian Liaoning P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fusheng","family":"Pang","sequence":"additional","affiliation":[{"name":"Liaoning Provence Key Lab of Genome Engineered Animal Models, Institute of Genome Engineered Animal Models for Human Diseases, National Center of Genetically Engineered Animal Models for International Research Dalian Medical University  Dalian Liaoning P.R. 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nian","family":"Liu","sequence":"additional","affiliation":[{"name":"Liaoning Provence Key Lab of Genome Engineered Animal Models, Institute of Genome Engineered Animal Models for Human Diseases, National Center of Genetically Engineered Animal Models for International Research Dalian Medical University  Dalian Liaoning P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0050-3794","authenticated-orcid":false,"given":"Shujing","family":"Wang","sequence":"additional","affiliation":[{"name":"Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences Dalian Medical University  Dalian Liaoning P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2694-1971","authenticated-orcid":false,"given":"Yingjie","family":"Wu","sequence":"additional","affiliation":[{"name":"Liaoning Provence Key Lab of Genome Engineered Animal Models, Institute of Genome Engineered Animal Models for Human Diseases, National Center of Genetically Engineered Animal Models for International Research Dalian Medical University  Dalian Liaoning P.R. China"},{"name":"Key Laboratory of Endocrine Glucose &amp; Lipids Metabolism and Brain Aging, Ministry of Education Shandong Provincial Hospital Affiliated to Shandong First Medical University &amp; Shandong Academy of Medical Sciences  Jinan Shandong P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1210\/endrev\/bnae030"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/s2468\u20102667(19)30019\u20102"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2003\u20100374"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.112041"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.1660579"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255\u2010023\u201000912\u2010w"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201057616\u2010w"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43587\u2010024\u201000652\u2010w"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201044026\u2010z"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.70207"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.ady3911"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.014308"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.026633"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101635"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ghir.2017.12.006"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2020.111063"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj20090390"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.13345"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2018.10.010"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31713"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.2337\/db11\u20101665"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556\u2010024\u201001543\u20103"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574\u2010019\u20100280\u20109"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1097\/hep.0000000000000307"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202409126"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqac129"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eng.2024.09.020"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2023.03.005"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.70655"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010020\u201003162\u2010w"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15691"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11357\u2010024\u201001426\u20103"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2019.05.020"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.64.2.355"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.14501"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201037214\u20104"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.2337\/db18\u20100363"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2023.155589"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.116"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12199\u2010010\u20100193\u20107"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13238"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2025.102983"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008054"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ado5887"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13968"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/jne.12854"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/lifemeta\/loaf037"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2024.01.015"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2024.102294"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2017.11.054"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12263\u2010018\u20100595\u20105"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.70407"}],"container-title":["Aging 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