{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:49:43Z","timestamp":1790016583577,"version":"4.0.1"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2025,3,22]],"date-time":"2025-03-22T00:00:00Z","timestamp":1742601600000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The active peptide hormone Ang II (angiotensin II) mediates the vast majority of the RAS (renin-angiotensin system) action, mainly through activation of AT1R (Angiotensin II type-1 receptor). AT1R expression peaks in newborn males and decreases toward the adult age, and it is shown to exhibit an inhibitory effect on hCG (human chorionic gonadotropin)-stimulated steroidogenesis in LCs (Leydig cells), as well as an promoting effect on smooth muscle and endothelial cell senescence. However, whether hyperactivation of the AT1R signaling exerts any effects on Leydig cell senescence, which could provide insights into hypogonadism mechanisms for aging males, remains unexplored. We herein reported that AT1R expression was significantly upregulated in aged human and rat testes. Transgenic overexpression of AT1R in LCs mimicked multiple late-onset hypogonadism phenotypes, including acceleration of Leydig cell senescence, defective steroidogenesis and spermatogenesis, and increased inflammation and oxidative stress. One of the core biochemical events underpinning AT1R action was the AT1R-induced enhancement of the interaction between MDM2 (murine double minute 2) and the p65 subunit of NF-\u03baB (nuclear factor-kappaB), consequently augmenting polyubiquitination and activation of p65, in a p38-dependent manner. Conversely, repression of AT1R activity ameliorated Leydig cell senescence and rescued testicular steroidogenesis in old rats. Together, forced expression of AT1R within the testicular interstitium potentiates aging-related traits in LCs, thereby leading to fertility impairment with defective steroidogenesis and spermatogenesis in male rodents. Our systematic analysis also indicates that blocking the Ang II\/AT1R signal might be beneficial in intervening disorders of late-onset hypogonadism in old males.<\/jats:p>","DOI":"10.1093\/gerona\/glaf004","type":"journal-article","created":{"date-parts":[[2025,3,23]],"date-time":"2025-03-23T11:13:56Z","timestamp":1742728436000},"source":"Crossref","is-referenced-by-count":2,"title":["Age-associated increase in AT1R expression in human testis and its intervention effects on Leydig cell senescence in aged rodents"],"prefix":"10.1093","author":[{"given":"Minye","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Gynaecology and Obstetrics, Xijing Hospital, Air Force Medical University (The Fourth Military Medical University) , Xi\u2019an 710032, P.R.","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhua","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Histology and Embryology, Basic Medical Science Academy , Air Force Medical University (The Fourth Military Medical University), Xi\u2019an 710032, P.R.","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Geng","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Histology and Embryology, Basic Medical Science Academy , Air Force Medical University (The Fourth Military Medical University), Xi\u2019an 710032, P.R.","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Histology and Embryology, Basic Medical Science Academy , Air Force Medical University (The Fourth Military Medical University), Xi\u2019an 710032, P.R.","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Histology and Embryology, Basic Medical Science Academy , Air Force Medical University (The Fourth Military Medical University), Xi\u2019an 710032, P.R.","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Gynaecology and Obstetrics, Xijing Hospital, Air Force Medical University (The Fourth Military Medical University) , Xi\u2019an 710032, P.R.","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Gynaecology and Obstetrics, Xijing Hospital, Air Force Medical University (The Fourth Military Medical University) , Xi\u2019an 710032, P.R.","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2487-3773","authenticated-orcid":false,"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Histology and Embryology, Basic Medical Science Academy , Air Force Medical University (The Fourth Military Medical University), Xi\u2019an 710032, P.R.","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,3,22]]},"container-title":["The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/biomedgerontology\/advance-article-pdf\/doi\/10.1093\/gerona\/glaf004\/62522196\/glaf004.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/biomedgerontology\/advance-article-pdf\/doi\/10.1093\/gerona\/glaf004\/62522196\/glaf004.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,23]],"date-time":"2025-03-23T11:13:57Z","timestamp":1742728437000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/biomedgerontology\/advance-article\/doi\/10.1093\/gerona\/glaf004\/8090236"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,22]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1093\/gerona\/glaf004","relation":{},"ISSN":["1079-5006","1758-535X"],"issn-type":[{"value":"1079-5006","type":"print"},{"value":"1758-535X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,22]]},"article-number":"glaf004"}}