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Angiopoietin\u2010like protein 8 (ANGPTL8) is a metabolic factor implicated in lipid metabolism and inflammation and has been associated with multiple aging\u2010related disorders. However, its direct role in adipose tissue senescence and organismal aging remains unclear. Here, we identify ANGPTL8 as a previously unrecognized regulator of adipose tissue aging through integrative analyzes of human cohorts, animal models, transcriptomics, and cellular studies. In a large human cohort, circulating ANGPTL8 levels were strongly associated with biological aging and mortality risk and significantly improved machine learning\u2013based models for age and survival prediction. Consistent with these findings, genetic deletion of\n                    <jats:italic>Angptl8<\/jats:italic>\n                    in mice extended lifespan, attenuated aging\u2010associated functional decline, and reduced senescence markers in adipose tissue. Transcriptomic analyzes revealed age\u2010dependent upregulation of ANGPTL8 in adipocytes accompanied by activation of pro\u2010senescent transcriptional programs. Mechanistically, ANGPTL8 directly interacted with AKT2 and activated the AKT\u2013mTOR\u2013S6K signaling pathway, thereby promoting cell\u2010autonomous adipocyte senescence. Genetic or pharmacological inhibition of this pathway abolished the pro\u2010senescent effects of ANGPTL8. Collectively, our findings identify ANGPTL8 as an endocrine regulator linking metabolic dysfunction to adipose tissue senescence and systemic aging, highlighting the ANGPTL8\u2013AKT2\u2013mTOR axis as a potential therapeutic target for delaying age\u2010associated functional decline.\n                  <\/jats:p>","DOI":"10.1111\/acel.70671","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T06:34:58Z","timestamp":1786948498000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An ANGPTL8\u2010AKT2\u2010mTOR Axis Drives Adipose Senescence and Aging\u2010Related Functional Decline"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1313-0946","authenticated-orcid":false,"given":"Yi","family":"He","sequence":"first","affiliation":[{"name":"Department of Endocrinology Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology  Wuhan Hubei China"},{"name":"Hubei Provincial Clinical Medical Research Center for Endocrinology and Metabolic Diseases  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limeng","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology  Wuhan Hubei China"},{"name":"Hubei Provincial Clinical Medical Research Center for Endocrinology and Metabolic Diseases  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"WenJun","family":"Ping","sequence":"additional","affiliation":[{"name":"Department of Metabolic and Bariatric Surgery The Third Xiangya Hospital, Central South University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Joint Bone Disease Surgery Changhai Hospital, Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology  Wuhan Hubei China"},{"name":"Hubei Provincial Clinical Medical Research Center for Endocrinology and Metabolic Diseases  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2860-5640","authenticated-orcid":false,"given":"Yaming","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology  Wuhan Hubei China"},{"name":"Hubei Provincial Clinical Medical Research Center for Endocrinology and Metabolic Diseases  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2829-945X","authenticated-orcid":false,"given":"Ranran","family":"Kan","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology  Wuhan Hubei China"},{"name":"Hubei Provincial Clinical Medical Research Center for Endocrinology and Metabolic Diseases  Wuhan Hubei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxi","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology  Wuhan Hubei China"},{"name":"Hubei Provincial Clinical Medical Research Center for Endocrinology and Metabolic Diseases  Wuhan Hubei 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