{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:53:42Z","timestamp":1790142822019,"version":"4.0.1"},"reference-count":67,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T00:00:00Z","timestamp":1725580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFA1104100"],"award-info":[{"award-number":["2022YFA1104100"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32130046"],"award-info":[{"award-number":["32130046"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171564"],"award-info":[{"award-number":["82171564"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82101669"],"award-info":[{"award-number":["82101669"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371611"],"award-info":[{"award-number":["82371611"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371609"],"award-info":[{"award-number":["82371609"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82301796"],"award-info":[{"award-number":["82301796"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Science Foundation of Guangdong Province, China","award":["2022A1515010371"],"award-info":[{"award-number":["2022A1515010371"]}]},{"name":"Major Project of Medical Science and Technology Development Research Center of National Health Planning Commission, China","award":["HDSL202001000"],"award-info":[{"award-number":["HDSL202001000"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>STUDY QUESTION<\/jats:title>\n                    <jats:p>What is the molecular landscape underlying the functional decline of human testicular ageing?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>SUMMARY ANSWER<\/jats:title>\n                    <jats:p>The present study provides a comprehensive single-cell transcriptomic atlas of testes from young and old humans and offers insights into the molecular mechanisms and potential targets for human testicular ageing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WHAT IS KNOWN ALREADY<\/jats:title>\n                    <jats:p>Testicular ageing is known to cause male age-related fertility decline and hypogonadism. Dysfunction of testicular cells has been considered as a key factor for testicular ageing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title>\n                    <jats:p>Human testicular biopsies were collected from three young individuals and three old individuals to perform single-cell RNA sequencing (scRNA-seq). The key results were validated in a larger cohort containing human testicular samples from 10 young donors and 10 old donors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n                    <jats:p>scRNA-seq was used to identify gene expression signatures for human testicular cells during ageing. Ageing-associated changes of gene expression in spermatogonial stem cells (SSCs) and Leydig cells (LCs) were analysed by gene set enrichment analysis and validated by immunofluorescent and functional assays. Cell\u2013cell communication analysis was performed using CellChat.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                    <jats:p>The single-cell transcriptomic landscape of testes from young and old men was surveyed, revealing age-related changes in germline and somatic niche cells. In-depth evaluation of the gene expression dynamics in germ cells revealed that the disruption of the base-excision repair pathway is a prominent characteristic of old SSCs, suggesting that defective DNA repair in SSCs may serve as a potential driver for increased de novo germline mutations with age. Further analysis of ageing-associated transcriptional changes demonstrated that stress-related changes and cytokine pathways accumulate in old somatic cells. Age-related impairment of redox homeostasis in old LCs was identified and pharmacological treatment with antioxidants alleviated this cellular dysfunction of LCs and promoted testosterone production. Lastly, our results revealed that decreased pleiotrophin signalling was a contributing factor for impaired spermatogenesis in testicular ageing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LARGE SCALE DATA<\/jats:title>\n                    <jats:p>The scRNA-seq sequencing and processed data reported in this paper were deposited at the Genome Sequence Archive (https:\/\/ngdc.cncb.ac.cn\/), under the accession number HRA002349.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                    <jats:p>Owing to the difficulty in collecting human testis tissue, the sample size was limited. Further in-depth functional and mechanistic studies are warranted in future.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                    <jats:p>These findings provide a comprehensive understanding of the cell type-specific mechanisms underlying human testicular ageing at a single-cell resolution, and suggest potential therapeutic targets that may be leveraged to address age-related male fertility decline and hypogonadism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n                    <jats:p>This work was supported by the National Key Research and Development Program of China (2022YFA1104100), the National Natural Science Foundation of China (32130046, 82171564, 82101669, 82371611, 82371609, 82301796), the Natural Science Foundation of Guangdong Province, China (2022A1515010371), the Major Project of Medical Science and Technology Development Research Center of National Health Planning Commission, China (HDSL202001000), the Open Project of NHC Key Laboratory of Male Reproduction and Genetics (KF202001), the Guangdong Province Regional Joint Fund-Youth Fund Project (2021A1515110921, 2022A1515111201), and the China Postdoctoral Science Foundation (2021M703736). The authors declare no conflict of interest.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/humrep\/deae199","type":"journal-article","created":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T14:36:26Z","timestamp":1724769386000},"page":"2189-2209","source":"Crossref","is-referenced-by-count":37,"title":["Single-cell RNA sequencing reveals transcriptomic landscape and potential targets for human testicular ageing"],"prefix":"10.1093","volume":"39","author":[{"given":"Kai","family":"Xia","sequence":"first","affiliation":[{"name":"Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou,","place":["China"]},{"name":"Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Luo","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Centre, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou,","place":["China"]},{"name":"Guangdong Key Laboratory of Reproductive Medicine , Guangzhou, Guangdong,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajie","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyuan","family":"He","sequence":"additional","affiliation":[{"name":"Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Dong","sequence":"additional","affiliation":[{"name":"Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou,","place":["China"]},{"name":"Reproductive Medicine Centre, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuren","family":"Chen","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Centre, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunlin","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Urology, Sun Yat-Sen University Cancer Centre , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0588-7600","authenticated-orcid":false,"given":"Yong","family":"Gao","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Centre, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou,","place":["China"]},{"name":"Guangdong Key Laboratory of Reproductive Medicine , Guangzhou, Guangdong,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanchen","family":"Ma","sequence":"additional","affiliation":[{"name":"Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuifeng","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yadong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiyun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dayu","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongcai","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Ke","sequence":"additional","affiliation":[{"name":"Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University , Guangzhou,","place":["China"]},{"name":"Guangdong Key Laboratory of Reproductive Medicine , Guangzhou, Guangdong,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University , Guangzhou,","place":["China"]},{"name":"National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqiang","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University , Guangzhou,","place":["China"]},{"name":"Guangdong Key Laboratory of Reproductive Medicine , Guangzhou, Guangdong,","place":["China"]},{"name":"National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang\u2019an","family":"Tu","sequence":"additional","affiliation":[{"name":"Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangzhou","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4969-2875","authenticated-orcid":false,"given":"Chunhua","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Urology and Andrology, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3409-5012","authenticated-orcid":false,"given":"Andy Peng","family":"Xiang","sequence":"additional","affiliation":[{"name":"Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University , Guangzhou,","place":["China"]},{"name":"National-Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat-Sen University , Guangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,9,6]]},"reference":[{"key":"2024100305525676500_deae199-B1","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1093\/humrep\/dead157","article-title":"Male reproductive ageing: a radical road to ruin","volume":"38","author":"Aitken","year":"2023","journal-title":"Hum Reprod"},{"key":"2024100305525676500_deae199-B2","doi-asserted-by":"crossref","first-page":"5205","DOI":"10.1038\/s41467-021-25544-0","article-title":"Aging, inflammation and DNA damage in the somatic testicular niche with idiopathic germ cell aplasia","volume":"12","author":"Alfano","year":"2021","journal-title":"Nat Commun"},{"key":"2024100305525676500_deae199-B3","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1172\/JCI95145","article-title":"Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives","volume":"128","author":"Baker","year":"2018","journal-title":"J Clin Invest"},{"key":"2024100305525676500_deae199-B4","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1038\/s41586-019-0969-x","article-title":"The single-cell transcriptional landscape of mammalian organogenesis","volume":"566","author":"Cao","year":"2019","journal-title":"Nature"},{"key":"2024100305525676500_deae199-B5","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.jsbmb.2003.10.007","article-title":"Aging alters the functional expression of enzymatic and non-enzymatic anti-oxidant defense systems in testicular rat Leydig cells","volume":"88","author":"Cao","year":"2004","journal-title":"J Steroid Biochem Mol Biol"},{"key":"2024100305525676500_deae199-B6","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.exger.2005.06.004","article-title":"Vitamin E, aging and Leydig cell steroidogenesis","volume":"40","author":"Chen","year":"2005","journal-title":"Exp Gerontol"},{"key":"2024100305525676500_deae199-B7","doi-asserted-by":"crossref","first-page":"4964","DOI":"10.1210\/en.2014-1406","article-title":"Peritubular myoid cells participate in male mouse spermatogonial stem cell maintenance","volume":"155","author":"Chen","year":"2014","journal-title":"Endocrinology"},{"key":"2024100305525676500_deae199-B8","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.jhazmat.2019.01.054","article-title":"Hydrogen sulfide exposure triggers chicken trachea inflammatory injury through oxidative stress-mediated FOS\/IL8 signaling","volume":"368","author":"Chen","year":"2019","journal-title":"J Hazard Mater"},{"key":"2024100305525676500_deae199-B9","doi-asserted-by":"crossref","first-page":"R159","DOI":"10.1530\/REP-14-0481","article-title":"Regulation of spermatogonial stem cell self-renewal and spermatocyte meiosis by Sertoli cell signaling","volume":"149","author":"Chen","year":"2015","journal-title":"Reproduction"},{"key":"2024100305525676500_deae199-B10","doi-asserted-by":"crossref","first-page":"102033","DOI":"10.1016\/j.redox.2021.102033","article-title":"Epigenetic regulation of TXNIP-mediated oxidative stress and NLRP3 inflammasome activation contributes to SAHH inhibition-aggravated diabetic nephropathy","volume":"45","author":"Dai","year":"2021","journal-title":"Redox Biol"},{"key":"2024100305525676500_deae199-B11","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1006\/abbi.2001.2705","article-title":"Pleiotrophin: a cytokine with diverse functions and a novel signaling pathway","volume":"397","author":"Deuel","year":"2002","journal-title":"Arch Biochem Biophys"},{"key":"2024100305525676500_deae199-B12","doi-asserted-by":"crossref","first-page":"100395","DOI":"10.1016\/j.xcrm.2021.100395","article-title":"Single-cell RNA-seq unravels alterations of the human spermatogonial stem cell compartment in patients with impaired spermatogenesis","volume":"2","author":"Di Persio","year":"2021","journal-title":"Cell Rep Med"},{"key":"2024100305525676500_deae199-B13","doi-asserted-by":"crossref","first-page":"101660","DOI":"10.1016\/j.tice.2021.101660","article-title":"ATF3 regulates oxidative stress and extracellular matrix degradation via p38\/Nrf2 signaling pathway in pelvic organ prolapse","volume":"73","author":"Feng","year":"2021","journal-title":"Tissue Cell"},{"key":"2024100305525676500_deae199-B14","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/s41573-021-00233-1","article-title":"Targeting oxidative stress in disease: promise and limitations of antioxidant therapy","volume":"20","author":"Forman","year":"2021","journal-title":"Nat Rev Drug Discov"},{"key":"2024100305525676500_deae199-B15","doi-asserted-by":"crossref","first-page":"14314","DOI":"10.1073\/pnas.1306752110","article-title":"Germ-line variant of human NTH1 DNA glycosylase induces genomic instability and cellular transformation","volume":"110","author":"Galick","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024100305525676500_deae199-B16","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1038\/s41422-018-0099-2","article-title":"The adult human testis transcriptional cell atlas","volume":"28","author":"Guo","year":"2018","journal-title":"Cell Res"},{"key":"2024100305525676500_deae199-B17","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.stem.2019.12.005","article-title":"The dynamic transcriptional cell atlas of testis development during human puberty","volume":"26","author":"Guo","year":"2020","journal-title":"Cell Stem Cell"},{"key":"2024100305525676500_deae199-B18","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.stem.2020.12.004","article-title":"Single-cell analysis of the developing human testis reveals somatic niche cell specification and fetal germline stem cell establishment","volume":"28","author":"Guo","year":"2021","journal-title":"Cell Stem Cell"},{"key":"2024100305525676500_deae199-B19","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.3390\/cells10112895","article-title":"Transcriptome analysis of testicular aging in mice","volume":"10","author":"Han","year":"2021","journal-title":"Cells"},{"key":"2024100305525676500_deae199-B20","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Hao","year":"2021","journal-title":"Cell"},{"key":"2024100305525676500_deae199-B21","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1016\/j.celrep.2012.11.005","article-title":"Pleiotrophin regulates the retention and self-renewal of hematopoietic stem cells in the bone marrow vascular niche (vol 2, pg 964, 2012)","volume":"2","author":"Himburg","year":"2012","journal-title":"Cell Reports"},{"key":"2024100305525676500_deae199-B22","doi-asserted-by":"crossref","first-page":"e12776","DOI":"10.1371\/journal.pone.0012776","article-title":"Inferring regulatory networks from expression data using tree-based methods","volume":"5","author":"Huynh-Thu","year":"2010","journal-title":"PLoS One"},{"key":"2024100305525676500_deae199-B23","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1007\/s11255-013-0610-0","article-title":"Quantitative histological analysis and ultrastructure of the aging human testis","volume":"46","author":"Jiang","year":"2014","journal-title":"Int Urol Nephrol"},{"key":"2024100305525676500_deae199-B24","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"Jin","year":"2021","journal-title":"Nat Commun"},{"key":"2024100305525676500_deae199-B25","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/S0015-0282(16)59959-2","article-title":"Effect of age on the composition of seminiferous tubular boundary tissue and on the volume of each component in humans","volume":"49","author":"Johnson","year":"1988","journal-title":"Fertil Steril"},{"key":"2024100305525676500_deae199-B26","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.arr.2014.10.007","article-title":"Consistent age-dependent declines in human semen quality: a systematic review and meta-analysis","volume":"19","author":"Johnson","year":"2015","journal-title":"Ageing Res Rev"},{"key":"2024100305525676500_deae199-B27","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1210\/er.2018-00178","article-title":"Aging and the male reproductive system","volume":"40","author":"Kaufman","year":"2019","journal-title":"Endocr Rev"},{"key":"2024100305525676500_deae199-B28","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1002\/j.1939-4640.2003.tb02661.x","article-title":"Balance of apoptosis and proliferation of germ cells related to spermatogenesis in aged men","volume":"24","author":"Kimura","year":"2003","journal-title":"J Androl"},{"key":"2024100305525676500_deae199-B29","doi-asserted-by":"crossref","first-page":"e13242","DOI":"10.1111\/acel.13242","article-title":"A germ cell-specific ageing pattern in otherwise healthy men","volume":"19","author":"Laurentino","year":"2020","journal-title":"Aging Cell"},{"key":"2024100305525676500_deae199-B30","doi-asserted-by":"crossref","first-page":"108566","DOI":"10.1016\/j.celrep.2020.108566","article-title":"Aging-associated alterations in mammary epithelia and stroma revealed by single-cell RNA sequencing","volume":"33","author":"Li","year":"2020","journal-title":"Cell Rep"},{"key":"2024100305525676500_deae199-B31","doi-asserted-by":"crossref","first-page":"5664","DOI":"10.1093\/nar\/gky326","article-title":"APE1 deficiency promotes cellular senescence and premature aging features","volume":"46","author":"Li","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"2024100305525676500_deae199-B32","doi-asserted-by":"crossref","first-page":"2666","DOI":"10.1073\/pnas.1519395113","article-title":"Regulation of seminiferous tubule-associated stem Leydig cells in adult rat testes","volume":"113","author":"Li","year":"2016","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024100305525676500_deae199-B33","doi-asserted-by":"crossref","first-page":"111389","DOI":"10.1016\/j.mce.2021.111389","article-title":"An autofluorescence-based isolation of Leydig cells for testosterone deficiency treatment","volume":"535","author":"Luo","year":"2021","journal-title":"Mol Cell Endocrinol"},{"key":"2024100305525676500_deae199-B34","doi-asserted-by":"crossref","first-page":"2454","DOI":"10.1073\/pnas.1521325113","article-title":"Visualizing the origins of selfish de novo mutations in individual seminiferous tubules of human testes","volume":"113","author":"Maher","year":"2016","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024100305525676500_deae199-B35","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1016\/j.ajhg.2021.09.001","article-title":"Comparative single-cell analysis of biopsies clarifies pathogenic mechanisms in Klinefelter syndrome","volume":"108","author":"Mahyari","year":"2021","journal-title":"Am J Hum Genet"},{"key":"2024100305525676500_deae199-B36","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1210\/er.2018-00140","article-title":"Testis development","volume":"40","author":"Makela","year":"2019","journal-title":"Endocr Rev"},{"key":"2024100305525676500_deae199-B37","doi-asserted-by":"crossref","first-page":"3114","DOI":"10.3390\/cells10113114","article-title":"Hallmarks of testicular aging: the challenge of anti-inflammatory and antioxidant therapies using natural and\/or pharmacological compounds to improve the physiopathological status of the aged male gonad","volume":"10","author":"Matzkin","year":"2021","journal-title":"Cells"},{"key":"2024100305525676500_deae199-B38","doi-asserted-by":"crossref","first-page":"2663","DOI":"10.1093\/humrep\/deaa271","article-title":"Age-related changes in human Leydig cell status","volume":"35","author":"Mularoni","year":"2020","journal-title":"Hum Reprod"},{"key":"2024100305525676500_deae199-B39","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1016\/j.devcel.2022.04.004","article-title":"Single-cell analysis of human testis aging and correlation with elevated body mass index","volume":"57","author":"Nie","year":"2022","journal-title":"Dev Cell"},{"key":"2024100305525676500_deae199-B40","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1515\/hsz-2018-0449","article-title":"Ageing and sources of transcriptional heterogeneity","volume":"400","author":"Nikopoulou","year":"2019","journal-title":"Biol Chem"},{"key":"2024100305525676500_deae199-B41","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1152\/physrev.00025.2011","article-title":"The germline stem cell niche unit in mammalian testes","volume":"92","author":"Oatley","year":"2012","journal-title":"Physiol Rev"},{"key":"2024100305525676500_deae199-B42","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1242\/dev.032243","article-title":"Colony stimulating factor 1 is an extrinsic stimulator of mouse spermatogonial stem cell self-renewal","volume":"136","author":"Oatley","year":"2009","journal-title":"Development"},{"key":"2024100305525676500_deae199-B43","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1002\/jemt.1060190209","article-title":"Ultrastructure of the aging human testis","volume":"19","author":"Paniagua","year":"1991","journal-title":"J Electron Microsc Tech"},{"key":"2024100305525676500_deae199-B44","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.mce.2008.11.004","article-title":"Aging of the human ovary and testis","volume":"299","author":"Perheentupa","year":"2009","journal-title":"Mol Cell Endocrinol"},{"key":"2024100305525676500_deae199-B45","doi-asserted-by":"crossref","first-page":"R89","DOI":"10.1530\/REP-20-0633","article-title":"Healthy ageing and spermatogenesis","volume":"161","author":"Pohl","year":"2021","journal-title":"Reproduction"},{"key":"2024100305525676500_deae199-B46","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1111\/andr.12665","article-title":"Ageing in men with normal spermatogenesis alters spermatogonial dynamics and nuclear morphology in Sertoli cells","volume":"7","author":"Pohl","year":"2019","journal-title":"Andrology"},{"key":"2024100305525676500_deae199-B47","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1038\/nrm.2017.53","article-title":"The multifaceted roles of PARP1 in DNA repair and chromatin remodelling","volume":"18","author":"Ray Chaudhuri","year":"2017","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2024100305525676500_deae199-B48","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1093\/gerona\/gly082","article-title":"Testicular aging: an overview of ultrastructural, cellular, and molecular alterations","volume":"74","author":"Santiago","year":"2019","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"2024100305525676500_deae199-B49","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1093\/humupd\/dmz006","article-title":"Spermatogonial stem cells: updates from specification to clinical relevance","volume":"25","author":"Sharma","year":"2019","journal-title":"Hum Reprod Update"},{"key":"2024100305525676500_deae199-B50","doi-asserted-by":"crossref","first-page":"7335","DOI":"10.1038\/s41467-022-34990-3","article-title":"Targeting APLN\/APJ restores blood-testis barrier and improves spermatogenesis in murine and human diabetic models","volume":"13","author":"Song","year":"2022","journal-title":"Nat Commun"},{"key":"2024100305525676500_deae199-B51","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.3390\/cells10061306","article-title":"Age-related alterations in the testicular proteome of a non-human primate","volume":"10","author":"Stockl","year":"2021","journal-title":"Cells"},{"key":"2024100305525676500_deae199-B52","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive integration of single-cell data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"2024100305525676500_deae199-B53","doi-asserted-by":"crossref","first-page":"D1083","DOI":"10.1093\/nar\/gkx1042","article-title":"Human Ageing Genomic Resources: new and updated databases","volume":"46","author":"Tacutu","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"2024100305525676500_deae199-B54","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.ceb.2020.07.005","article-title":"A single-cell view of spermatogonial stem cells","volume":"67","author":"Tan","year":"2020","journal-title":"Curr Opin Cell Biol"},{"key":"2024100305525676500_deae199-B55","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1007\/s11596-011-0247-0","article-title":"Morphology of rat testis preserved in three different fixatives","volume":"31","author":"Tu","year":"2011","journal-title":"J Huazhong Univ Sci Technolog Med Sci"},{"key":"2024100305525676500_deae199-B56","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.cell.2020.01.009","article-title":"Single-cell transcriptomic atlas of primate ovarian aging","volume":"180","author":"Wang","year":"2020","journal-title":"Cell"},{"key":"2024100305525676500_deae199-B57","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.redox.2018.02.011","article-title":"Astrocytic CCAAT\/Enhancer-binding protein delta contributes to reactive oxygen species formation in neuroinflammation","volume":"16","author":"Wang","year":"2018","journal-title":"Redox Biol"},{"key":"2024100305525676500_deae199-B58","doi-asserted-by":"crossref","first-page":"100792","DOI":"10.1016\/j.xcrm.2022.100792","article-title":"AAV-mediated gene therapy produces fertile offspring in the Lhcgr-deficient mouse model of Leydig cell failure","volume":"3","author":"Xia","year":"2022","journal-title":"Cell Rep Med"},{"key":"2024100305525676500_deae199-B59","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1038\/s41593-019-0491-3","article-title":"Single-cell transcriptomic profiling of the aging mouse brain","volume":"22","author":"Ximerakis","year":"2019","journal-title":"Nat Neurosci"},{"key":"2024100305525676500_deae199-B60","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1038\/s41586-021-04369-3","article-title":"A human brain vascular atlas reveals diverse mediators of Alzheimer\u2019s risk","volume":"603","author":"Yang","year":"2022","journal-title":"Nature"},{"key":"2024100305525676500_deae199-B61","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1007\/s10815-018-1148-y","article-title":"Reproductive genetics and the aging male","volume":"35","author":"Yatsenko","year":"2018","journal-title":"J Assist Reprod Genet"},{"key":"2024100305525676500_deae199-B62","doi-asserted-by":"crossref","first-page":"6734","DOI":"10.1073\/pnas.96.12.6734","article-title":"A dominant-negative pleiotrophin mutant introduced by homologous recombination leads to germ-cell apoptosis in male mice","volume":"96","author":"Zhang","year":"1999","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024100305525676500_deae199-B63","doi-asserted-by":"crossref","first-page":"5683","DOI":"10.1038\/s41467-020-19414-4","article-title":"Single-cell analysis of developing and azoospermia human testicles reveals central role of Sertoli cells","volume":"11","author":"Zhao","year":"2020","journal-title":"Nat Commun"},{"key":"2024100305525676500_deae199-B64","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.redox.2016.12.036","article-title":"Tert-butyl hydroperoxide (t-BHP) induced apoptosis and necroptosis in endothelial cells: roles of NOX4 and mitochondrion","volume":"11","author":"Zhao","year":"2017","journal-title":"Redox Biol"},{"key":"2024100305525676500_deae199-B65","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1007\/s13238-020-00762-2","article-title":"A human circulating immune cell landscape in aging and COVID-19","volume":"11","author":"Zheng","year":"2020","journal-title":"Protein Cell"},{"key":"2024100305525676500_deae199-B66","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1093\/biolre\/ioy059","article-title":"Leydig cells: formation, function, and regulation","volume":"99","author":"Zirkin","year":"2018","journal-title":"Biol Reprod"},{"key":"2024100305525676500_deae199-B67","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.devcel.2020.11.002","article-title":"A single-cell transcriptomic atlas of human skin aging","volume":"56","author":"Zou","year":"2021","journal-title":"Dev Cell"}],"container-title":["Human Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/humrep\/article-pdf\/39\/10\/2189\/59401613\/deae199.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/humrep\/article-pdf\/39\/10\/2189\/59401613\/deae199.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T01:53:56Z","timestamp":1727920436000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/humrep\/article\/39\/10\/2189\/7750559"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,6]]},"references-count":67,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,9,6]]},"published-print":{"date-parts":[[2024,10,1]]}},"URL":"https:\/\/doi.org\/10.1093\/humrep\/deae199","relation":{},"ISSN":["0268-1161","1460-2350"],"issn-type":[{"value":"0268-1161","type":"print"},{"value":"1460-2350","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,10]]},"published":{"date-parts":[[2024,9,6]]}}}