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Dietary citrate extends the lifespan of <jats:styled-content style=\"fixed-case\"><jats:italic>Drosophila melanogaster<\/jats:italic><\/jats:styled-content> and <jats:styled-content style=\"fixed-case\"><jats:italic>Caenorhabditis elegans<\/jats:italic><\/jats:styled-content> as well as improves the memory of mice injured by a high\u2010fat diet (HFD); whether it alleviates vascular aging and age\u2010related vascular diseases; however, remains unknown. Here, we showed that dietary supplementation of citrate delayed vascular aging, as evidenced by maintaining the integrity of elastic fibers and decreasing the level of the aging\u2010related marker, CDKN1A (p21). Functionally, citrate improved the sensitivity to endothelial\u2010dependent vasodilators and lowered blood pressure, and in HFD\u2010fed <jats:italic>ApoE<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice, it reduced the size of atherosclerotic plaques, decreased the necrotic core area and vulnerability index in aortic root plaques. Additionally, citrate decreased the frailty index, increased bone density, and improved maximal grip strength and balance speed in both aged and HFD\u2010fed <jats:italic>ApoE<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice. Mechanistically, we showed that citrate exposure delayed human umbilical vein endothelial cell senescence with a decreased percentage of cells stained with senescence\u2010associated \u03b2\u2010galactosidase and p21 levels. Moreover, citrate activated AMPK\u2010related pathways and reversed senescence\u2010related mitochondrial dysfunction in basal respiration, maximal respiration, and ATP production and reduced the production of reactive oxygen species (ROS). The citrate\u2010promoted beneficial effects were abolished due to inactivated AMPK and the increased mitochondrial ROS. Thus, we demonstrate that dietary citrate delays vascular aging and alleviates age\u2010related vascular diseases by improving mitochondrial function via activation of AMPK\u2010related pathways. Citrate may have potential clinical implications for interventions against vascular aging and age\u2010related vascular diseases.<\/jats:p>","DOI":"10.1111\/acel.70213","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T10:43:02Z","timestamp":1756982582000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Dietary Citrate Restores Age\u2010Related Endothelial Cell Mitochondrial Dysfunction and Alleviates Atherosclerosis"],"prefix":"10.1111","volume":"24","author":[{"given":"Ya","family":"Zhao","sequence":"first","affiliation":[{"name":"Aging and Vascular Diseases, Human Aging Research Institute (HARI) and School of Life Science Nanchang University, and Jiangxi Province Key Laboratory of Aging and Disease  Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia\u2010Yu","family":"Qiu","sequence":"additional","affiliation":[{"name":"Aging and Vascular Diseases, Human Aging Research Institute (HARI) and School of Life Science Nanchang University, and Jiangxi Province Key Laboratory of Aging and Disease  Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Wu","sequence":"additional","affiliation":[{"name":"Aging and Vascular Diseases, Human Aging Research Institute (HARI) and School of Life Science Nanchang University, and Jiangxi Province Key Laboratory of Aging and Disease  Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1197-3452","authenticated-orcid":false,"given":"Xue\u2010Ting","family":"Gong","sequence":"additional","affiliation":[{"name":"Aging and Vascular Diseases, Human Aging Research Institute (HARI) and School of Life Science Nanchang University, and Jiangxi Province Key Laboratory of Aging and Disease  Nanchang Jiangxi 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Nanchang University, and Jiangxi Province Key Laboratory of Aging and Disease  Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue\u2010Er","family":"Li","sequence":"additional","affiliation":[{"name":"Aging and Vascular Diseases, Human Aging Research Institute (HARI) and School of Life Science Nanchang University, and Jiangxi Province Key Laboratory of Aging and Disease  Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An\u2010Dong","family":"Wu","sequence":"additional","affiliation":[{"name":"Aging and Vascular Diseases, Human Aging Research Institute (HARI) and School of Life Science Nanchang University, and Jiangxi Province Key Laboratory of Aging and Disease  Nanchang Jiangxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing\u2010Jing","family":"Duan","sequence":"additional","affiliation":[{"name":"Human Aging Research Institute (HARI) and School of Life Science Nanchang 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