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Aging\u2010induced liver function alterations contribute to systemic susceptibility to aging\u2010related diseases. However, the molecular mechanisms of liver aging remain insufficiently understood. In this study, we performed bulk RNA\u2010Seq and single\u2010cell RNA\u2010Seq analyses to investigate the underlying mechanisms of the aging\u2010induced liver function changes. We found that liver inflammation, glucose intolerance, and liver fat deposition were aggravated in old mice. Aging significantly increased pro\u2010inflammation in hepatic macrophages. Furthermore, we found that Kupffer cells (KCs) were the major driver to induce pro\u2010inflammation in hepatic macrophages during aging. In KCs, aging significantly increased pro\u2010inflammatory levels; in monocyte\u2010derived macrophages (MDMs), aging had a limited effect on pro\u2010inflammation but led to a functional quiescence in antigen presentation and phagosome process. In addition, we identified an aging\u2010responsive KC\u2010specific (ARKC) gene set that potentially mediates aging\u2010induced pro\u2010inflammation in KCs. Interestingly, FOXO1 activity was significantly increased in the liver of old mice. FOXO1 inhibition by AS1842856 significantly alleviated glucose intolerance, hepatic steatosis, and systemic inflammation in old mice. FOXO1 inhibition significantly attenuated aging\u2010induced pro\u2010inflammation in KCs partially through downregulation of ARKC genes. However, FOXO1 inhibition had a limited effect on aging\u2010induced functional quiescence in MDMs. These results indicate that aging induces pro\u2010inflammation in liver mainly through targeting KCs and FOXO1 is a key player in aging\u2010induced pro\u2010inflammation in KCs. Thus, FOXO1 could be a potential therapeutic target for the treatment of age\u2010associated chronic diseases.<\/jats:p>","DOI":"10.1111\/acel.13968","type":"journal-article","created":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T02:01:12Z","timestamp":1692669672000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Suppression of FOXO1 attenuates inflamm\u2010aging and improves liver function during aging"],"prefix":"10.1111","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5519-8443","authenticated-orcid":false,"given":"Wanbao","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Nutrition, College of Agriculture and Life Sciences Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da Mi","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Nutrition, College of Agriculture and Life Sciences Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Nutrition, College of Agriculture and Life Sciences Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqi","family":"Ai","sequence":"additional","affiliation":[{"name":"Department of Nutrition, College of Agriculture and Life Sciences Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Nutrition, College of Agriculture and Life Sciences Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahina","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Statistics Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James J.","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Veterinary Integrative Biosciences Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wesley A.","family":"Brashear","sequence":"additional","affiliation":[{"name":"High Performance Research Computing Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Nutrition, College of Agriculture and Life Sciences Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5126-731X","authenticated-orcid":false,"given":"Shaodong","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Nutrition, College of Agriculture and Life Sciences Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,8,21]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/gls145"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1210\/edrv-14-1-72"},{"key":"e_1_2_9_4_1","volume-title":"scGEAToolbox: A Matlab toolbox for single\u2010cell RNA sequencing data analysis","author":"Cai J. 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