{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T15:12:27Z","timestamp":1778253147976,"version":"3.51.4"},"reference-count":37,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T00:00:00Z","timestamp":1749168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371049"],"award-info":[{"award-number":["82371049"]}],"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":["STKJ2023001"],"award-info":[{"award-number":["STKJ2023001"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Special Strategic Project on Innovative Science and Technology of Guangdong Province","award":["82371049"],"award-info":[{"award-number":["82371049"]}]},{"name":"Special Strategic Project on Innovative Science and Technology of Guangdong Province","award":["STKJ2023001"],"award-info":[{"award-number":["STKJ2023001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Older age is a risk factor for glaucoma, in which progressive retinal ganglion cell (RGC) loss leads to visual field defects and irreversible visual impairment and even blindness. We recently identified the involvement of cellular senescence in RGC cell death post-optic nerve injury. Here we further aimed to delineate the profile of RGC survival in mice with aging, a physiological process with increasing cellular senescence. The numbers of senescent cells in the ganglion cell layer (GCL) significantly and progressively increased starting at 8 months of age. Yet, significant reduction of ganglion cell complex layer thickness began in the 10-month-old mice, and significant reduction in the number of RGCs began in the 12-month-old mice as compared to the 2-month-old mice. Meanwhile, pyroptosis and ferroptosis markers as well as cellular senescence-related cell cycle arrest proteins p15Ink4b, p16Ink4a, p21Cip1, and p53 were significantly and progressively increased in GCL. In contrast, there were no significant changes in dendritic field, complexity, and branches with increasing ages. Comparing between the 2- and 16-month-old mouse retinas, the differentially expressed genes were involved in the pathways of neurodegeneration, innate immunity, and mitochondrial ATP synthesis. In summary, this study revealed the gradual increase in senescent cells as well as pyroptosis and ferroptosis with progressive RGC reduction in mice with aging. Cellular senescence and the related cell death pathways are potential targets for age-related RGC reduction.<\/jats:p>","DOI":"10.3390\/ijms26125436","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T06:11:08Z","timestamp":1749190268000},"page":"5436","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Profile of Retinal Ganglion Cell Death and Cellular Senescence in Mice with Aging"],"prefix":"10.3390","volume":"26","author":[{"given":"Wen-Ying","family":"Wang","sequence":"first","affiliation":[{"name":"Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou 515041, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Bin","sequence":"additional","affiliation":[{"name":"Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou 515041, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanxuan","family":"Xu","sequence":"additional","affiliation":[{"name":"Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou 515041, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Si","family":"Chen","sequence":"additional","affiliation":[{"name":"Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou 515041, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuyi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou 515041, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaowan","family":"Chen","sequence":"additional","affiliation":[{"name":"Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou 515041, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingjie","family":"Cao","sequence":"additional","affiliation":[{"name":"Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou 515041, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kunliang","family":"Qiu","sequence":"additional","affiliation":[{"name":"Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou 515041, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7863-7229","authenticated-orcid":false,"given":"Tsz Kin","family":"Ng","sequence":"additional","affiliation":[{"name":"Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou 515041, China"},{"name":"Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1016\/j.ophtha.2014.05.013","article-title":"Global prevalence of glaucoma and projections of glaucoma burden through 2040: A systematic review and meta-analysis","volume":"121","author":"Tham","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9636897221123512","DOI":"10.1177\/09636897221123512","article-title":"Diversified Treatment Options of Adult Stem Cells for Optic Neuropathies","volume":"31","author":"Tan","year":"2022","journal-title":"Cell Transplant."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1001\/jama.2014.3192","article-title":"The pathophysiology and treatment of glaucoma: A review","volume":"311","author":"Weinreb","year":"2014","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1016\/S0140-6736(17)31469-1","article-title":"Glaucoma","volume":"390","author":"Jonas","year":"2017","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.optom.2016.02.003","article-title":"Glaucoma history and risk factors","volume":"10","author":"McMonnies","year":"2017","journal-title":"J. Optom."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4437","DOI":"10.1167\/iovs.08-1753","article-title":"Age-related losses of retinal ganglion cells and axons","volume":"49","author":"Harwerth","year":"2008","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5151","DOI":"10.1167\/iovs.02-1101","article-title":"Quantitative analysis of retinal ganglion cell (RGC) loss in aging DBA\/2NNia glaucomatous mice: Comparison with RGC loss in aging C57\/BL6 mice","volume":"44","author":"Danias","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s12035-017-0734-9","article-title":"The Retina of Osteopontin deficient Mice in Aging","volume":"55","author":"Ruzafa","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1159\/000515447","article-title":"Age-Related Alterations of Proteins in Albino Wistar Rat Retina","volume":"210","author":"Mester","year":"2021","journal-title":"Cells Tissues Organs"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Kashiwagi, K., Ito, S., Maeda, S., and Kato, G. (2017). A Ser75-to-Asp phospho-mimicking mutation in Src accelerates ageing-related loss of retinal ganglion cells in mice. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-16872-7"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1159\/000073762","article-title":"Numbers of neurons in the retinal ganglion cell layer of the rat do not change throughout life","volume":"49","author":"Harman","year":"2003","journal-title":"Gerontology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1016\/j.exer.2010.10.003","article-title":"Retinal ganglion cell numbers and delayed retinal ganglion cell death in the P23H rat retina","volume":"91","author":"Agudo","year":"2010","journal-title":"Exp. Eye Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"109159","DOI":"10.1016\/j.exer.2022.109159","article-title":"Longitudinal and simultaneous profiling of 11 modes of cell death in mouse retina post-optic nerve injury","volume":"222","author":"Yao","year":"2022","journal-title":"Exp. Eye Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e13719","DOI":"10.1111\/cpr.13719","article-title":"Cellular senescence mediates retinal ganglion cell survival regulation post-optic nerve crush injury","volume":"57","author":"Yao","year":"2024","journal-title":"Cell Prolif."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s41580-020-00314-w","article-title":"Cellular senescence in ageing: From mechanisms to therapeutic opportunities","volume":"22","author":"Krizhanovsky","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Haverkamp, S., Reinhard, K., Peichl, L., and Mietsch, M. (2022). No evidence for age-related alterations in the marmoset retina. Front. Neuroanat., 16.","DOI":"10.3389\/fnana.2022.945295"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/j.bcp.2011.11.031","article-title":"Dopamine-3 receptor modulates intraocular pressure: Implications for glaucoma","volume":"83","author":"Bucolo","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"16033","DOI":"10.1523\/JNEUROSCI.3580-11.2011","article-title":"Age-related alterations in neurons of the mouse retina","volume":"31","author":"Samuel","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Lee, P.Y., Zhao, D., Wong, V.H.Y., Chrysostomou, V., Crowston, J.G., and Bui, B.V. (2022). The Effect of Aging on Retinal Function and Retinal Ganglion Cell Morphology Following Intraocular Pressure Elevation. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.859265"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1038\/s41591-019-0673-2","article-title":"Undulating changes in human plasma proteome profiles across the lifespan","volume":"25","author":"Lehallier","year":"2019","journal-title":"Nat. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1007\/s40520-015-0484-3","article-title":"p15(INK4b) regulates cell cycle signaling in hippocampal astrocytes of aged rats","volume":"28","author":"Wang","year":"2016","journal-title":"Aging Clin. Exp. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1038\/s41580-024-00738-8","article-title":"SenNet recommendations for detecting senescent cells in different tissues","volume":"25","author":"Suryadevara","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_23","first-page":"341","article-title":"p53 regulates apoptotic retinal ganglion cell death induced by N-methyl-D-aspartate","volume":"8","author":"Li","year":"2002","journal-title":"Mol. Vis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4479","DOI":"10.1167\/iovs.19-27396","article-title":"Cyclin-Dependent Kinase Inhibitor 2b Mediates Excitotoxicity-Induced Death of Retinal Ganglion Cells","volume":"60","author":"Tawarayama","year":"2019","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e2752","DOI":"10.1038\/cddis.2017.169","article-title":"P16INK4a upregulation mediated by TBK1 induces retinal ganglion cell senescence in ischemic injury","volume":"8","author":"Li","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1002\/dvdy.74","article-title":"Senescence-associated \u03b2-galactosidase activity in the developing avian retina","volume":"248","year":"2019","journal-title":"Dev. Dyn."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"eaaw0254","DOI":"10.1126\/sciadv.aaw0254","article-title":"The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype","volume":"5","author":"Hari","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/j.cell.2014.04.007","article-title":"Mechanisms and functions of inflammasomes","volume":"157","author":"Lamkanfi","year":"2014","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1111\/j.1749-6632.2000.tb06651.x","article-title":"Inflamm-aging. An evolutionary perspective on immunosenescence","volume":"908","author":"Franceschi","year":"2000","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1038\/s41591-018-0092-9","article-title":"Senolytics improve physical function and increase lifespan in old age","volume":"24","author":"Xu","year":"2018","journal-title":"Nat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"109787","DOI":"10.1016\/j.exer.2024.109787","article-title":"Combined treatment of human mesenchymal stem cells and green tea extract on retinal ganglion cell regeneration in rats after optic nerve injury","volume":"239","author":"Yang","year":"2024","journal-title":"Exp. Eye Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"109708","DOI":"10.1016\/j.exer.2023.109708","article-title":"Longitudinal in vivo evaluation of retinal ganglion cell complex layer and dendrites in mice with experimental autoimmune encephalomyelitis","volume":"237","author":"Qian","year":"2023","journal-title":"Exp. Eye Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.1093\/bioinformatics\/btr390","article-title":"Simple Neurite Tracer: Open source software for reconstruction, visualization and analysis of neuronal processes","volume":"27","author":"Longair","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1038\/nmeth.3125","article-title":"Neuronal morphometry directly from bitmap images","volume":"11","author":"Ferreira","year":"2014","journal-title":"Nat. Methods"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Yuan, X.L., Chen, S.L., Xu, Y., Yao, Y., Liang, J.J., Zhuang, X., Hald, E.S., and Ng, T.K. (2023). Green tea extract enhances retinal ganglion cell survival and axonal regeneration in rats with optic nerve injury. Green tea extract enhances retinal ganglion cell survival and axonal regeneration in rats with optic nerve injury. J. Nutr. Biochem., 117.","DOI":"10.1016\/j.jnutbio.2023.109333"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Dennis, G., Sherman, B.T., Hosack, D.A., Yang, J., Gao, W., Lane, H.C., and Lempicki, R.A. (2003). DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol., 4.","DOI":"10.1186\/gb-2003-4-5-p3"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/12\/5436\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:47:32Z","timestamp":1760032052000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/12\/5436"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,6]]},"references-count":37,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["ijms26125436"],"URL":"https:\/\/doi.org\/10.3390\/ijms26125436","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,6]]}}}