{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T19:02:03Z","timestamp":1789585323360,"version":"build-2803163510"},"reference-count":48,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"38","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32330040, 82350710222"],"award-info":[{"award-number":["32330040, 82350710222"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National key R&D program of China","award":["2023YFC3605400"],"award-info":[{"award-number":["2023YFC3605400"]}]},{"name":"Shenzhen Science and Technology Program","award":["KQTD20221101093608028"],"award-info":[{"award-number":["KQTD20221101093608028"]}]},{"name":"Shenzhen Government Basic Research Program","award":["JCYJ20200109150717745"],"award-info":[{"award-number":["JCYJ20200109150717745"]}]},{"name":"Shenzhen Government Basic Research Program","award":["JCYJ20220531100802005"],"award-info":[{"award-number":["JCYJ20220531100802005"]}]},{"name":"Shenzhen Science and Technology Program","award":["82171583"],"award-info":[{"award-number":["82171583"]}]},{"name":"Guangdong Basic and Applied Basic Research Foundation","award":["2023A1515030296, 2026A1515010174"],"award-info":[{"award-number":["2023A1515030296, 2026A1515010174"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,9,18]]},"abstract":"<jats:p>\n                    Age-related microvascular dysfunction disrupts nutrient homeostasis and waste clearance, leading to organ failure. However, a critical gap remains in our understanding of the specific molecular drivers of vascular deterioration and how they orchestrate organism-wide aging. Here, we identify progressive activation of the CCAAT\/enhancer-binding protein \u03b2 (C\/EBP\u03b2)\/asparagine endopeptidase (AEP) pathway in aging vascular endothelial cells contributes to vascular degeneration and lifespan reduction. Endothelial-specific C\/EBP\u03b2 or AEP overexpression accelerated vascular aging and shortened lifespan in mice. Mechanistically, AEP mediates proteolytic cleavage of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide adenine dinucleotide (oxidised form, NAD\n                    <jats:sup>+<\/jats:sup>\n                    ) biosynthesis, resulting in systemic NAD\n                    <jats:sup>+<\/jats:sup>\n                    depletion and senescence that elicits both central and peripheral vascular dysfunction and ultimately systemic aging. Genetic ablation of AEP or expression of AEP-resistant NAMPT N136A mutant significantly ameliorated vascular aging and extended lifespan in endothelial-specific Tie 2-C\/EBP\u03b2 transgenic mice. Pharmacologically, AEP inhibitor CP#11A or nicotinamide mononucleotide (NMN) supplementation alleviated age-related vascular decline, with CP#11A showing superior efficacy. These findings support a model in which endothelial senescence contributes to vascular dysfunction and systemic aging mediated by C\/EBP\u03b2\/AEP signaling, and establish C\/EBP\u03b2\/AEP as a therapeutic target to preserve vascular integrity and mitigate systemic frailty in aging populations.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aed1961","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T18:02:56Z","timestamp":1789581776000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Endothelial C\/EBP\u03b2\/AEP pathway drives vascular deterioration and systemic aging"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5624-9361","authenticated-orcid":true,"given":"Bowei","family":"Li","sequence":"first","affiliation":[{"name":"Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China."},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3776-2749","authenticated-orcid":true,"given":"Shuke","family":"Nie","sequence":"additional","affiliation":[{"name":"Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0856-4831","authenticated-orcid":true,"given":"Mengmeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4849-5294","authenticated-orcid":true,"given":"Jiawei","family":"An","sequence":"additional","affiliation":[{"name":"Faculty of Life and Health Sciences, Shenzhen University of Advanced Technology (SUAT), Shenzhen, Guangdong 518055, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1306-6829","authenticated-orcid":true,"given":"Zhengjiang","family":"Qian","sequence":"additional","affiliation":[{"name":"Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4051-3997","authenticated-orcid":true,"given":"Xin","family":"Meng","sequence":"additional","affiliation":[{"name":"Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6810-6149","authenticated-orcid":true,"given":"Laura E.","family":"Edgington-Mitchell","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne Victoria 3010, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6708-1472","authenticated-orcid":true,"given":"Zhentao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, 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