{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T14:46:15Z","timestamp":1787323575918,"version":"build-2736575974"},"reference-count":115,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82470657"],"award-info":[{"award-number":["82470657"]}],"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":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>During aging, hepatic structural, metabolic, and regulatory impairments collectively contribute to the decline of hepatic and systemic function. As a core hepatic physiological process, ammonia metabolism is essential for maintaining systemic nitrogen homeostasis. However, how ammonia metabolism is altered during aging, and whether these changes contribute to hepatic and systemic decline, remain insufficiently understood. In this review, current evidence linking hepatic ammonia metabolism to liver aging is summarized. The major pathways of hepatic ammonia disposal, including the urea cycle and glutamine synthesis, are first outlined. Age\u2010related changes in these pathways are then discussed, with emphasis on mitochondrial dysfunction, altered post\u2010translational regulation, transcriptional and epigenetic remodeling, and disruption of metabolic zonation. Emerging evidence that ammonia functions not only as a nitrogen waste product but also as a bioactive stress signal is also reviewed. In this context, ammonia has been implicated in mitochondrial injury, senescence\u2010associated signaling, proteostasis defects, and inflammatory and fibrogenic remodeling. The systemic consequences of ammonia dysregulation are further considered, particularly along the liver\u2013brain, liver\u2013muscle, and liver\u2013gut axes. Finally, current and emerging therapeutic strategies are evaluated, including ammonia\u2010lowering agents, senotherapeutics, and microbiota\u2010directed approaches. Collectively, this review identify ammonia metabolism as an underappreciated but potentially axis for understanding liver aging, thereby providing a framework for future mechanistic and translational studies.<\/jats:p>","DOI":"10.1111\/acel.70639","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T19:27:03Z","timestamp":1784662023000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ammonia Metabolism in the Aging Liver: Emerging Mechanistic Insights"],"prefix":"10.1111","volume":"25","author":[{"given":"Heng","family":"Zhang","sequence":"first","affiliation":[{"name":"Experimental Medicine Center, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"},{"name":"Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyu","family":"Liang","sequence":"additional","affiliation":[{"name":"Experimental Medicine Center, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"},{"name":"Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anding","family":"Liu","sequence":"additional","affiliation":[{"name":"Experimental Medicine Center, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"},{"name":"Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11357\u2010024\u201001137\u20109"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2012.07.007"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010019\u20101373\u20102"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10522\u2010024\u201010153\u20103"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2006.03.015"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575\u2010019\u20100134\u2010x"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255\u2010019\u20100109\u20109"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/lifemeta\/load028"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545\u2010017\u20100088\u20105"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.08.004"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.15252\/msb.202211002"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545\u2010012\u20109546\u20102"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nurt.2010.05.015"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jceh.2018.05.004"},{"key":"e_1_2_14_16_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00037.2016"},{"key":"e_1_2_14_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes9020108"},{"key":"e_1_2_14_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010026\u201002576\u2010w"},{"key":"e_1_2_14_19_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.02.064"},{"key":"e_1_2_14_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4000"},{"key":"e_1_2_14_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11319"},{"key":"e_1_2_14_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glt169"},{"key":"e_1_2_14_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu10111564"},{"key":"e_1_2_14_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2012.11.005"},{"key":"e_1_2_14_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2016.06.004"},{"key":"e_1_2_14_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.06.023"},{"key":"e_1_2_14_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30890"},{"key":"e_1_2_14_28_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1463187"},{"key":"e_1_2_14_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255\u2010020\u201000323\u20101"},{"key":"e_1_2_14_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2025.08.021"},{"key":"e_1_2_14_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43587\u2010024\u201000652\u2010w"},{"key":"e_1_2_14_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574\u2010018\u20100059\u20104"},{"key":"e_1_2_14_33_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0267647"},{"key":"e_1_2_14_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575\u2010024\u201000970\u20109"},{"key":"e_1_2_14_35_1","doi-asserted-by":"publisher","DOI":"10.1055\/a\u20102637\u20102549"},{"key":"e_1_2_14_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.proghi.2006.12.001"},{"key":"e_1_2_14_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2006.11.081"},{"key":"e_1_2_14_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28852"},{"key":"e_1_2_14_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature21065"},{"key":"e_1_2_14_40_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj2670281"},{"key":"e_1_2_14_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572\u2010022\u201000366\u20106"},{"key":"e_1_2_14_42_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2007.122176"},{"key":"e_1_2_14_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2022.100754"},{"key":"e_1_2_14_44_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M203126200"},{"key":"e_1_2_14_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44355\u2010024\u201000011\u2010x"},{"key":"e_1_2_14_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.11.019"},{"key":"e_1_2_14_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2025.09.009"},{"key":"e_1_2_14_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/lifemedi\/lnaf019"},{"key":"e_1_2_14_49_1","doi-asserted-by":"publisher","DOI":"10.3350\/cmh.2019.0015"},{"key":"e_1_2_14_50_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb5916"},{"key":"e_1_2_14_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xgen.2025.101133"},{"key":"e_1_2_14_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44319\u2010026\u201000740\u20105"},{"key":"e_1_2_14_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.10.039"},{"key":"e_1_2_14_54_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ado1648"},{"key":"e_1_2_14_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2017.01.012"},{"key":"e_1_2_14_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29107"},{"key":"e_1_2_14_57_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.154089"},{"key":"e_1_2_14_58_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv047"},{"key":"e_1_2_14_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(02)08524\u20100"},{"key":"e_1_2_14_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575\u2010025\u201001099\u2010z"},{"key":"e_1_2_14_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2024.10.003"},{"key":"e_1_2_14_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010023\u201001502\u20108"},{"key":"e_1_2_14_63_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2021.44279"},{"key":"e_1_2_14_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.11.001"},{"key":"e_1_2_14_65_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12829"},{"key":"e_1_2_14_66_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11010\u2010015\u20102448\u20105"},{"key":"e_1_2_14_67_1","doi-asserted-by":"publisher","DOI":"10.2174\/1566524011313040005"},{"key":"e_1_2_14_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2024.116034"},{"key":"e_1_2_14_69_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11357\u2010025\u201001601\u20100"},{"key":"e_1_2_14_70_1","doi-asserted-by":"publisher","DOI":"10.14309\/ajg.0000000000002008"},{"key":"e_1_2_14_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.08.063"},{"key":"e_1_2_14_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2023.112154"},{"key":"e_1_2_14_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.02.026"},{"key":"e_1_2_14_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2016.04.010"},{"key":"e_1_2_14_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.02.032"},{"key":"e_1_2_14_76_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43587\u2010023\u201000513\u2010y"},{"key":"e_1_2_14_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2020.10.003"},{"key":"e_1_2_14_78_1","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.16603"},{"key":"e_1_2_14_79_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1089769"},{"key":"e_1_2_14_80_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15691"},{"key":"e_1_2_14_81_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2015.08.012"},{"key":"e_1_2_14_82_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2024.0784"},{"key":"e_1_2_14_83_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32408"},{"key":"e_1_2_14_84_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601563"},{"key":"e_1_2_14_85_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01667"},{"key":"e_1_2_14_86_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1317049110"},{"key":"e_1_2_14_87_1","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13918"},{"key":"e_1_2_14_88_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.181812"},{"key":"e_1_2_14_89_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2010.03.040"},{"key":"e_1_2_14_90_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575\u2010024\u201000913\u20104"},{"key":"e_1_2_14_91_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajg.2024.07.016"},{"key":"e_1_2_14_92_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201803061"},{"key":"e_1_2_14_93_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964\u2010025\u201002328\u20103"},{"key":"e_1_2_14_94_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29410"},{"key":"e_1_2_14_95_1","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000001451"},{"key":"e_1_2_14_96_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1714670115"},{"key":"e_1_2_14_97_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12061"},{"key":"e_1_2_14_98_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12070"},{"key":"e_1_2_14_99_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2025.02.033"},{"key":"e_1_2_14_100_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29396"},{"key":"e_1_2_14_101_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2017.03.002"},{"key":"e_1_2_14_102_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2023.100780"},{"key":"e_1_2_14_103_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jceh.2018.08.010"},{"key":"e_1_2_14_104_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255\u2010021\u201000483\u20108"},{"key":"e_1_2_14_105_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00726\u2010009\u20100269\u20100"},{"key":"e_1_2_14_106_1","doi-asserted-by":"publisher","DOI":"10.1093\/jmcb\/mjac016"},{"key":"e_1_2_14_107_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2025.5623"},{"key":"e_1_2_14_108_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2023.04.005"},{"key":"e_1_2_14_109_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276\u2010020\u201000504\u20108"},{"key":"e_1_2_14_110_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.772174"},{"key":"e_1_2_14_111_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M600272200"},{"key":"e_1_2_14_112_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms242417514"},{"key":"e_1_2_14_113_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967\u2010023\u201004367\u20101"},{"key":"e_1_2_14_114_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2025.101397"},{"key":"e_1_2_14_115_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom12040580"},{"key":"e_1_2_14_116_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010024\u201001839\u20108"}],"container-title":["Aging Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70639","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/acel.70639","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70639","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T14:10:17Z","timestamp":1787321417000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/acel.70639"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,21]]},"references-count":115,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1111\/acel.70639"],"URL":"https:\/\/doi.org\/10.1111\/acel.70639","archive":["Portico"],"relation":{},"ISSN":["1474-9718","1474-9726"],"issn-type":[{"value":"1474-9718","type":"print"},{"value":"1474-9726","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,21]]},"assertion":[{"value":"2026-04-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70639"}}