{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:50:39Z","timestamp":1792525839658,"version":"4.5.0"},"reference-count":198,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NIDCR","award":["R01DE029468"],"award-info":[{"award-number":["R01DE029468"]}]},{"name":"NIH\/NIA","award":["RO1AG087335"],"award-info":[{"award-number":["RO1AG087335"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cellular senescence is a fundamental biological process characterized by stable cell cycle arrest, resistance to apoptosis, and the acquisition of a pro-inflammatory senescence-associated secretory phenotype (SASP). While senescence plays essential roles in development, tissue homeostasis, and tumor suppression, its accumulation with age and chronic stress contributes to tissue dysfunction and disease. In the oral cavity, where tissues are continuously exposed to mechanical stress, microbial challenge, and environmental insults, senescence has emerged as a critical regulator of both health and pathology. This review provides an overview of the defining hallmarks of cellular senescence, the molecular mechanisms driving its onset, and its physiological and pathological consequences, with a particular focus on oral tissues. We highlight the beneficial roles of senescence in maintaining oral tissue integrity, facilitating wound repair, suppressing malignant transformation, and promoting immune-mediated clearance of damaged cells. Conversely, we discuss the detrimental effects of persistent senescent cell accumulation, including oral aging phenotypes, chronic inflammation, alveolar bone loss, periodontal breakdown, salivary gland dysfunction, and contributions to oral carcinogenesis. Finally, we examine emerging therapeutic strategies targeting senescence in oral disease management, including senolytic and senomorphic approaches, immune-based clearance mechanisms, and gene- and cell-based interventions aimed at delaying or modulating senescence. Understanding the dualistic nature of cellular senescence in the oral environment may inform novel preventive and therapeutic strategies to promote oral health and mitigate age- and disease-associated oral pathologies.<\/jats:p>","DOI":"10.3390\/ijms27052269","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T10:24:34Z","timestamp":1772447074000},"page":"2269","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Role of Cellular Senescence in Oral Health and Disease"],"prefix":"10.3390","volume":"27","author":[{"given":"Mahmoud","family":"Elashiry","sequence":"first","affiliation":[{"name":"Periodontics Department, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3246-6206","authenticated-orcid":false,"given":"Celine Joyce","family":"Cornelius Timothius","sequence":"additional","affiliation":[{"name":"Periodontics Department, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8803-0439","authenticated-orcid":false,"given":"Rizwana","family":"Zaman","sequence":"additional","affiliation":[{"name":"Periodontics Department, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2099-2651","authenticated-orcid":false,"given":"Marisa","family":"Elliott","sequence":"additional","affiliation":[{"name":"Periodontics Department, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryce","family":"Crosby","sequence":"additional","affiliation":[{"name":"Periodontics Department, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keshav","family":"Bhat","sequence":"additional","affiliation":[{"name":"Periodontics Department, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2649-9850","authenticated-orcid":false,"given":"Karim M.","family":"Saad","sequence":"additional","affiliation":[{"name":"Periodontics Department, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5034-4109","authenticated-orcid":false,"given":"Ranya","family":"Elsayed","sequence":"additional","affiliation":[{"name":"Periodontics Department, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,28]]},"reference":[{"key":"ref_1","first-page":"e80442","article-title":"Navigating the Future of Elderly Healthcare: A Comprehensive Analysis of Aging Populations and Mortality Trends Using National Inpatient Sample (NIS) Data (2010\u20132024)","volume":"17","author":"Shreya","year":"2025","journal-title":"Cureus"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41514-024-00136-6","article-title":"Cost of care for Alzheimer\u2019s disease and related dementias in the United States: 2016 to 2060","volume":"10","author":"Nandi","year":"2024","journal-title":"npj Aging"},{"key":"ref_3","unstructured":"Merriam-Webster (2025, December 20). Senescence. Available online: https:\/\/www.merriam-webster.com\/dictionary\/senescence."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/0014-4827(61)90192-6","article-title":"The serial cultivation of human diploid cell strains","volume":"25","author":"Hayflick","year":"1961","journal-title":"Exp. Cell Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1007\/BF02616174","article-title":"Cell size in aging monolayer cultures","volume":"13","author":"Greenberg","year":"1977","journal-title":"In Vitro"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/0014-4827(84)90679-7","article-title":"Increased organization of cytoskeleton accompanying the aging of human fibroblasts in vitro","volume":"154","author":"Wang","year":"1984","journal-title":"Exp. Cell Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4220","DOI":"10.18632\/aging.204072","article-title":"Senescence-associated morphological profiles (SAMPs): An image-based phenotypic profiling method for evaluating the inter and intra model heterogeneity of senescence","volume":"14","author":"Wallis","year":"2022","journal-title":"Aging"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S107","DOI":"10.3233\/JAD-161221","article-title":"The DNA Damage Response in Neurons: Die by Apoptosis or Survive in a Senescence-Like State?","volume":"60","author":"Fielder","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1186\/s12985-023-02203-y","article-title":"DNA damage response(DDR): A link between cellular senescence and human cytomegalovirus","volume":"20","author":"Wu","year":"2023","journal-title":"Virol. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3923","DOI":"10.1038\/s41467-018-06308-9","article-title":"Persistent repair intermediates induce senescence","volume":"9","author":"Feringa","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/s41420-023-01583-y","article-title":"Lack of apoptosis leads to cellular senescence and tumorigenesis in Drosophila epithelial cells","volume":"9","author":"Pinal","year":"2023","journal-title":"Cell Death Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1083\/jcb.200904105","article-title":"Real-time in vivo imaging of p16Ink4a reveals cross talk with p53","volume":"186","author":"Yamakoshi","year":"2009","journal-title":"J. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Mijit, M., Caracciolo, V., Melillo, A., Amicarelli, F., and Giordano, A. (2020). Role of p53 in the Regulation of Cellular Senescence. Biomolecules, 10.","DOI":"10.3390\/biom10030420"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.1101\/gad.1971610","article-title":"The essence of senescence","volume":"24","author":"Kuilman","year":"2010","journal-title":"Genes. Dev."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Nousis, L., Kanavaros, P., and Barbouti, A. (2023). Oxidative Stress-Induced Cellular Senescence: Is Labile Iron the Connecting Link?. Antioxidants, 12.","DOI":"10.3390\/antiox12061250"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1091\/mbc.e05-08-0701","article-title":"Senescence of human fibroblasts after psoralen photoactivation is mediated by ATR kinase and persistent DNA damage foci at telomeres","volume":"17","author":"Hovest","year":"2006","journal-title":"Mol. Biol. Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/ncb1095","article-title":"Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks","volume":"6","author":"Sedelnikova","year":"2004","journal-title":"Nat. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3","DOI":"10.18632\/aging.100871","article-title":"Markers of cellular senescence. Telomere shortening as a marker of cellular senescence","volume":"8","author":"Bernadotte","year":"2016","journal-title":"Aging"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/S0092-8674(03)00401-X","article-title":"Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence","volume":"113","author":"Narita","year":"2003","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Basisty, N., Kale, A., Jeon, O.H., Kuehnemann, C., Payne, T., Rao, C., Holtz, A., Shah, S., Sharma, V., and Ferrucci, L. (2020). A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3000599"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1172\/JCI64098","article-title":"Cellular senescence and the senescent secretory phenotype: Therapeutic opportunities","volume":"123","author":"Tchkonia","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.18632\/aging.100971","article-title":"Unbiased analysis of senescence associated secretory phenotype (SASP) to identify common components following different genotoxic stresses","volume":"8","author":"Alessio","year":"2016","journal-title":"Aging"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Elsayed, R., Elashiry, M., Liu, Y., El-Awady, A., Hamrick, M., and Cutler, C.W. (2021). Porphyromonas gingivalis Provokes Exosome Secretion and Paracrine Immune Senescence in Bystander Dendritic Cells. Front. Cell. Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.669989"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"136","DOI":"10.14336\/AD.2022.0623","article-title":"Microbially-Induced Exosomes from Dendritic Cells Promote Paracrine Immune Senescence: Novel Mechanism of Bone Degenerative Disease in Mice","volume":"14","author":"Elsayed","year":"2023","journal-title":"Aging Dis."},{"key":"ref_25","first-page":"1340_6038","article-title":"Oral Microbially-induced Exosomes Cross Blood-Brain Barrier Contributing to Neuroinflammation and Alzheimer\u2019s Disease Pathogenesis","volume":"212","author":"Elsayed","year":"2024","journal-title":"J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/nature10599","article-title":"Senescence surveillance of pre-malignant hepatocytes limits liver cancer development","volume":"479","author":"Kang","year":"2011","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"398","DOI":"10.4161\/onci.19128","article-title":"Immune surveillance of pre-cancerous senescent hepatocytes limits hepatocellular carcinoma development","volume":"1","author":"Yevsa","year":"2012","journal-title":"Oncoimmunology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1093\/carcin\/bgs124","article-title":"Immune surveillance of senescent cells\u2014Biological significance in cancer- and non-cancer pathologies","volume":"33","author":"Hoenicke","year":"2012","journal-title":"Carcinogenesis"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e13707","DOI":"10.1111\/acel.13707","article-title":"The lysosomal proteome of senescent cells contributes to the senescence secretome","volume":"21","author":"Rovira","year":"2022","journal-title":"Aging Cell"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Valieva, Y., Ivanova, E., Fayzullin, A., Kurkov, A., and Igrunkova, A. (2022). Senescence-Associated \u03b2-Galactosidase Detection in Pathology. Diagnostics, 12.","DOI":"10.3390\/diagnostics12102309"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1111\/j.1474-9726.2006.00199.x","article-title":"Senescence-associated beta-galactosidase is lysosomal beta-galactosidase","volume":"5","author":"Lee","year":"2006","journal-title":"Aging Cell"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Curnock, R., and Carroll, B. (2025). Senescent cell survival relies on upregulation of lysosomal quality control mechanisms. bioRxiv.","DOI":"10.2139\/ssrn.5243514"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1083\/jcb.201610113","article-title":"Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing","volume":"216","author":"Carroll","year":"2017","journal-title":"J. Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.cell.2019.10.005","article-title":"Cellular Senescence: Defining a Path Forward","volume":"179","author":"Gorgoulis","year":"2019","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2652","DOI":"10.1016\/j.cub.2017.07.033","article-title":"Unmasking Transcriptional Heterogeneity in Senescent Cells","volume":"27","author":"Melov","year":"2017","journal-title":"Curr. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.18632\/aging.100991","article-title":"Aging of mice is associated with p16(Ink4a)- and \u03b2-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells","volume":"8","author":"Hall","year":"2016","journal-title":"Aging"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Faragher, R.G.A. (2021). Simple Detection Methods for Senescent Cells: Opportunities and Challenges. Front. Aging, 2.","DOI":"10.3389\/fragi.2021.686382"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4150","DOI":"10.1016\/j.cell.2024.05.059","article-title":"Guidelines for minimal information on cellular senescence experimentation in vivo","volume":"187","author":"Ogrodnik","year":"2024","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/s42003-024-06263-w","article-title":"Replication stress as a driver of cellular senescence and aging","volume":"7","author":"Herr","year":"2024","journal-title":"Commun. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"111229","DOI":"10.1016\/j.mad.2020.111229","article-title":"Oncogene-induced senescence: From biology to therapy","volume":"187","author":"Zhu","year":"2020","journal-title":"Mech. Ageing Dev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1038\/aps.2017.198","article-title":"Oncogene-induced senescence: A double edged sword in cancer","volume":"39","author":"Liu","year":"2018","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_42","first-page":"e846","article-title":"Evaluation of p53, caspase-3, Bcl-2, and Ki-67 markers in oral squamous cell carcinoma and premalignant epithelium in a sample from Alava Province (Spain)","volume":"18","year":"2013","journal-title":"Med. Oral Patol. Oral Cir. Bucal"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"104738","DOI":"10.1016\/j.archoralbio.2020.104738","article-title":"High p16(INK4a) immunoexpression is not HPV dependent in oral leukoplakia","volume":"115","author":"Tomo","year":"2020","journal-title":"Arch. Oral. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Parkinson, E.K., and Prime, S.S. (2022). Oral Senescence: From Molecular Biology to Clinical Research. Front. Dent. Med., 3.","DOI":"10.3389\/fdmed.2022.822397"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Niklander, S.E., Ar\u00e1nguiz, P., Faunes, F., and Mart\u00ednez-Flores, R. (2023). Aging and oral squamous cell carcinoma development: The role of cellular senescence. Front. Oral. Health, 4.","DOI":"10.3389\/froh.2023.1285276"},{"key":"ref_46","first-page":"100034","article-title":"Senescence and oral cancer: From mechanisms to therapeutic opportunities","volume":"1","author":"Yang","year":"2025","journal-title":"Transl. Dent. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1158\/0008-5472.CAN-05-1716","article-title":"The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms","volume":"66","author":"Bavik","year":"2006","journal-title":"Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/S0014-4827(03)00308-2","article-title":"Novel mechanisms of sublethal oxidant toxicity: Induction of premature senescence in human fibroblasts confers tumor promoter activity","volume":"290","author":"Dilley","year":"2003","journal-title":"Exp. Cell Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"12072","DOI":"10.1073\/pnas.211053698","article-title":"Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging","volume":"98","author":"Krtolica","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3117","DOI":"10.1158\/0008-5472.CAN-06-3452","article-title":"Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion","volume":"67","author":"Liu","year":"2007","journal-title":"Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.1080\/15384101.2019.1652047","article-title":"Chemotherapy-induced senescence, an adaptive mechanism driving resistance and tumor heterogeneity","volume":"18","author":"Guillon","year":"2019","journal-title":"Cell Cycle"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1038\/s41419-021-04454-5","article-title":"Early senescence and production of senescence-associated cytokines are major determinants of radioresistance in head-and-neck squamous cell carcinoma","volume":"12","author":"Schoetz","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1667\/RR14445.1","article-title":"Ionizing Radiation-Induced Endothelial Cell Senescence and Cardiovascular Diseases","volume":"186","author":"Wang","year":"2016","journal-title":"Radiat. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1038\/s41419-020-03074-9","article-title":"Cellular senescence contributes to radiation-induced hyposalivation by affecting the stem\/progenitor cell niche","volume":"11","author":"Peng","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1158\/0008-5472.CAN-15-1671","article-title":"Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation","volume":"76","author":"Marmary","year":"2016","journal-title":"Cancer Res."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Reyes, A., Ortiz, G., Duarte, L.F., Fern\u00e1ndez, C., Hern\u00e1ndez-Armengol, R., Palacios, P.A., Prado, Y., Andrade, C.A., Rodriguez-Guilarte, L., and Kalergis, A.M. (2023). Contribution of viral and bacterial infections to senescence and immunosenescence. Front. Cell. Infect. Microbiol., 13.","DOI":"10.3389\/fcimb.2023.1229098"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2356","DOI":"10.1101\/gad.227512.113","article-title":"Cell fusion induced by ERVWE1 or measles virus causes cellular senescence","volume":"27","author":"Chuprin","year":"2013","journal-title":"Genes. Dev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"21838","DOI":"10.18632\/aging.203560","article-title":"SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3","volume":"13","author":"Tripathi","year":"2021","journal-title":"Aging"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/s43587-022-00170-7","article-title":"SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response","volume":"2","author":"Tsuji","year":"2022","journal-title":"Nat. Aging"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/omi.12432","article-title":"Fusobacterium nucleatum triggers senescence phenotype in gingival epithelial cells","volume":"39","author":"Shelling","year":"2024","journal-title":"Mol. Oral Microbiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.job.2024.01.012","article-title":"Oral infection with Porphyromonas gingivalis augmented gingival epithelial barrier molecules alteration with aging","volume":"66","author":"Giri","year":"2024","journal-title":"J. Oral Biosci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"115220","DOI":"10.1016\/j.bone.2019.115220","article-title":"LPS-induced premature osteocyte senescence: Implications in inflammatory alveolar bone loss and periodontal disease pathogenesis","volume":"132","author":"Rowsey","year":"2020","journal-title":"Bone"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"112609","DOI":"10.1016\/j.exger.2024.112609","article-title":"High glucose-induced senescence contributes to tubular epithelial cell damage in diabetic nephropathy","volume":"197","author":"Xu","year":"2024","journal-title":"Exp. Gerontol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Wan, Y., Liu, Z., Wu, A., Khan, A.H., Zhu, Y., Ding, S., Li, X., Zhao, Y., Dai, X., and Zhou, J. (2022). Hyperglycemia Promotes Endothelial Cell Senescence through AQR\/PLAU Signaling Axis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052879"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"30924","DOI":"10.1038\/s41598-024-81878-x","article-title":"[Gly14]-Humanin ameliorates high glucose-induced endothelial senescence via SIRT6","volume":"14","author":"Li","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Zheng, L., Li, M., and Li, H. (2024). High Glucose Promotes and Aggravates the Senescence and Dysfunction of Vascular Endothelial Cells in Women with Hyperglycemia in Pregnancy. Biomolecules, 14.","DOI":"10.3390\/biom14030329"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"18807","DOI":"10.1074\/jbc.RA119.010648","article-title":"Hyperglycemia-induced inflamm-aging accelerates gingival senescence via NLRC4 phosphorylation","volume":"294","author":"Zhang","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"4730","DOI":"10.7150\/thno.98763","article-title":"Apoptotic vesicle-mediated senolytics requires mechanical loading","volume":"14","author":"Xue","year":"2024","journal-title":"Theranostics"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3941","DOI":"10.1007\/s11357-025-01507-x","article-title":"Substrate stiffness dictates unique doxorubicin-induced senescence-associated secretory phenotypes and transcriptomic signatures in human pulmonary fibroblasts","volume":"47","author":"Du","year":"2025","journal-title":"Geroscience"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/s41368-023-00228-1","article-title":"RANKL+ senescent cells under mechanical stress: A therapeutic target for orthodontic root resorption using senolytics","volume":"15","author":"Zhou","year":"2023","journal-title":"Int. J. Oral Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/nrm3823","article-title":"Cellular senescence: From physiology to pathology","volume":"15","author":"Serrano","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1016\/j.cell.2013.10.019","article-title":"Programmed cell senescence during mammalian embryonic development","volume":"155","author":"Maraver","year":"2013","journal-title":"Cell"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1016\/j.cell.2013.10.041","article-title":"Senescence is a developmental mechanism that contributes to embryonic growth and patterning","volume":"155","author":"Storer","year":"2013","journal-title":"Cell"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"aaf4445","DOI":"10.1126\/science.aaf4445","article-title":"Tissue damage and senescence provide critical signals for cellular reprogramming in vivo","volume":"354","author":"Mosteiro","year":"2016","journal-title":"Science"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.stem.2016.11.020","article-title":"Injury-Induced Senescence Enables In Vivo Reprogramming in Skeletal Muscle","volume":"20","author":"Chiche","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Andrade, A.M., Sun, M., Gasek, N.S., Hargis, G.R., Sharafieh, R., and Xu, M. (2022). Role of Senescent Cells in Cutaneous Wound Healing. Biology, 11.","DOI":"10.3390\/biology11121731"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1016\/j.devcel.2014.11.012","article-title":"An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA","volume":"31","author":"Demaria","year":"2014","journal-title":"Dev. Cell"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"O\u2019Reilly, S., Markiewicz, E., and Idowu, O.C. (2024). Aging, senescence, and cutaneous wound healing-a complex relationship. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1429716"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"627","DOI":"10.18632\/aging.100201","article-title":"Cellular senescence controls fibrosis in wound healing","volume":"2","author":"Jun","year":"2010","journal-title":"Aging"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"200309","DOI":"10.1098\/rsob.200309","article-title":"Senescent cells and macrophages: Key players for regeneration?","volume":"10","author":"Elder","year":"2020","journal-title":"Open Biol."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Wilkinson, H.N., and Hardman, M.J. (2020). Senescence in Wound Repair: Emerging Strategies to Target Chronic Healing Wounds. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00773"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1111\/his.13260","article-title":"DNA damage marker phosphorylated histone H2AX is a potential predictive marker for progression of epithelial dysplasia of the oral cavity","volume":"71","author":"Leung","year":"2017","journal-title":"Histopathology"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.tcb.2024.06.007","article-title":"Immune surveillance of senescence: Potential application to age-related diseases","volume":"35","author":"Wang","year":"2025","journal-title":"Trends Cell Biol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.cell.2008.06.049","article-title":"Senescence of activated stellate cells limits liver fibrosis","volume":"134","author":"Krizhanovsky","year":"2008","journal-title":"Cell"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1007\/s10522-024-10114-w","article-title":"Inhibitory immune checkpoints suppress the surveillance of senescent cells promoting their accumulation with aging and in age-related diseases","volume":"25","author":"Salminen","year":"2024","journal-title":"Biogerontology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"159","DOI":"10.3109\/13685538.2013.789014","article-title":"Oral diagnostics: An integral component to geriatric health care","volume":"16","author":"Kishore","year":"2013","journal-title":"Aging Male"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.jdsr.2013.09.001","article-title":"Nutrition and oral status in elderly people","volume":"50","author":"Yoshida","year":"2014","journal-title":"Jpn. Dent. Sci. Rev."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Samouillan, V., Ober, C., and Lacoste-Ferr\u00e9, M.H. (2025). Impact of Aging and Pathologies on Human Oral Mucosa: Preliminary Investigation of Biophysical Markers from Thermal and Vibrational Analyses. Biomolecules, 15.","DOI":"10.3390\/biom15070978"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Pe\u00f1a-Oyarz\u00fan, D., San Martin, C., Hern\u00e1ndez-C\u00e1ceres, M.P., Lavandero, S., Morselli, E., Budini, M., Burgos, P.V., and Criollo, A. (2022). Autophagy in aging-related oral diseases. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.903836"},{"key":"ref_90","first-page":"272","article-title":"Age-induced changes in the oral mucosa and their therapeutic consequences","volume":"33","author":"Breustedt","year":"1983","journal-title":"Int. Dent. J."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1038\/nm.4000","article-title":"Cellular senescence in aging and age-related disease: From mechanisms to therapy","volume":"21","author":"Childs","year":"2015","journal-title":"Nat. Med."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Wang, A.S., and Dreesen, O. (2018). Biomarkers of Cellular Senescence and Skin Aging. Front. Genet., 9.","DOI":"10.3389\/fgene.2018.00247"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1007\/s10856-007-3340-y","article-title":"Mechanical properties of human enamel as a function of age and location in the tooth","volume":"19","author":"Park","year":"2008","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.jdent.2013.11.025","article-title":"The effects of ageing on the biomechanical properties of root dentine and fracture","volume":"42","author":"Xu","year":"2014","journal-title":"J. Dent."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1177\/0022034510393347","article-title":"Autophagic activity and aging in human odontoblasts","volume":"90","author":"Couve","year":"2011","journal-title":"J. Dent. Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/j.1741-2358.2004.00009.x","article-title":"Clinical studies on the appearance of natural anterior teeth in young and old adults","volume":"21","author":"Hartmann","year":"2004","journal-title":"Gerodontology"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"289","DOI":"10.21873\/invivo.11474","article-title":"Oxidative Stress and Oral Mucosal Diseases: An Overview","volume":"33","author":"Sardaro","year":"2019","journal-title":"In Vivo"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"4393460","DOI":"10.1155\/2019\/4393460","article-title":"Salivary Antioxidant Barrier, Redox Status, and Oxidative Damage to Proteins and Lipids in Healthy Children, Adults, and the Elderly","volume":"2019","author":"Maciejczyk","year":"2019","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s12979-023-00400-5","article-title":"Senescence-associated secretory phenotypes in mesenchymal cells contribute to cytotoxic immune response in oral lichen planus","volume":"20","author":"Ijima","year":"2023","journal-title":"Immun. Ageing"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"9","DOI":"10.4103\/ijpm.ijpm_864_21","article-title":"Senescence in oral lichen planus as assessed by the immunohistochemical evaluation of senescence marker protein-30 (Regucalcin)","volume":"66","author":"Peter","year":"2023","journal-title":"Indian J. Pathol. Microbiol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"155411","DOI":"10.1016\/j.prp.2024.155411","article-title":"Prx1\/PHB2 axis mediates mitophagy in oral leukoplakia cellular senescence","volume":"260","author":"Lu","year":"2024","journal-title":"Pathol.-Res. Pract."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1038\/s41514-025-00200-9","article-title":"Characterization of senescence and nuclear reorganization in aging gingival cells","volume":"11","author":"Ormeno","year":"2025","journal-title":"NPJ Aging"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Yue, Z., Nie, L., Zhao, P., Ji, N., Liao, G., and Wang, Q. (2022). Senescence-associated secretory phenotype and its impact on oral immune homeostasis. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1019313"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1146\/annurev-pathol-121808-102144","article-title":"The senescence-associated secretory phenotype: The dark side of tumor suppression","volume":"5","author":"Desprez","year":"2010","journal-title":"Annu. Rev. Pathol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1111\/odi.14642","article-title":"Immunosenescence and inflammaging: Conspiracies against alveolar bone turnover","volume":"30","author":"Zhou","year":"2024","journal-title":"Oral. Dis."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Gonz\u00e1lez-Osuna, L., Sierra-Cristancho, A., Cafferata, E.A., Melgar-Rodr\u00edguez, S., Rojas, C., Carvajal, P., Cortez, C., and Vernal, R. (2022). Senescent CD4(+)CD28(-) T Lymphocytes as a Potential Driver of Th17\/Treg Imbalance and Alveolar Bone Resorption During Periodontitis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052543"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1002\/JPER.20-0529","article-title":"Senescent cells exacerbate chronic inflammation and contribute to periodontal disease progression in old mice","volume":"92","author":"Eckhardt","year":"2021","journal-title":"J. Periodontol."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Chen, S., Zhou, D., Liu, O., Chen, H., Wang, Y., and Zhou, Y. (2022). Cellular Senescence and Periodontitis: Mechanisms and Therapeutics. Biology, 11.","DOI":"10.3390\/biology11101419"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Chu, X., Elashiry, M., Carroll, A., Cornelius Timothius, C.J., Cutler, C.W., and Elsayed, R. (2025). The Role of Senescence in Experimental Periodontitis at the Causal Level: An in Vivo Study. Cells, 14.","DOI":"10.3390\/cells14030226"},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Clark, D., Radaic, A., and Kapila, Y. (2022). Cellular Mechanisms of Inflammaging and Periodontal Disease. Front. Dent. Med., 3.","DOI":"10.3389\/fdmed.2022.844865"},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Kim, S.J., Batra, C., Yoshii, H., Hamada, Y., Ueki, Y., Eckert, G.J., John, V., and Kittaka, M. (2025). Upregulation of senescence-associated gene expression levels in human gingival tissue affected by periodontitis. J. Periodontol., 1\u201313.","DOI":"10.1002\/jper.11393"},{"key":"ref_112","first-page":"1279","article-title":"Cellular senescence with SASP in periodontal ligament cells triggers inflammation in aging periodontal tissue","volume":"15","author":"Ikegami","year":"2023","journal-title":"Aging"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1007\/s10753-024-02014-5","article-title":"ROS-Induced Gingival Fibroblast Senescence: Implications in Exacerbating Inflammatory Responses in Periodontal Disease","volume":"47","author":"Guo","year":"2024","journal-title":"Inflammation"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"RP96908","DOI":"10.7554\/eLife.96908","article-title":"CD81+ senescent-like fibroblasts exaggerate inflammation and activate neutrophils via C3\/C3aR1 axis in periodontitis","volume":"13","author":"Fu","year":"2025","journal-title":"eLife"},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Aquino-Martinez, R., Khosla, S., Farr, J.N., and Monroe, D.G. (2020). Periodontal Disease and Senescent Cells: New Players for an Old Oral Health Problem?. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21207441"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"5977","DOI":"10.1007\/s00784-023-05211-y","article-title":"Porphyromonas gingivalis enhances the senescence-induced increase of 5-alpha reductase in gingival fibroblasts","volume":"27","author":"Orbak","year":"2023","journal-title":"Clin. Oral Investig."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1111\/omi.12167","article-title":"Caveolin-1 serves as a negative effector in senescent human gingival fibroblasts during Fusobacterium nucleatum infection","volume":"32","author":"Ahn","year":"2017","journal-title":"Mol. Oral Microbiol."},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Elashiry, M., Elsayed, R., and Cutler, C.W. (2021). Exogenous and Endogenous Dendritic Cell-Derived Exosomes: Lessons Learned for Immunotherapy and Disease Pathogenesis. Cells, 11.","DOI":"10.3390\/cells11010115"},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Elashiry, M., Carroll, A., Yuan, J., Liu, Y., Hamrick, M., Cutler, C.W., Wang, Q., and Elsayed, R. (2024). Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood-Brain Barrier. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25084509"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"eaau3333","DOI":"10.1126\/sciadv.aau3333","article-title":"Porphyromonas gingivalis in Alzheimer\u2019s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors","volume":"5","author":"Dominy","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"3763","DOI":"10.1007\/s10753-025-02317-1","article-title":"Inflammatory Association between Periodontal Disease and Systemic Health","volume":"48","author":"Hasan","year":"2025","journal-title":"Inflammation"},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Jiang, Y., Xu, L., Zhao, X., Shen, H., Qiu, C., He, Z., Song, Z., and Zhou, W. (2025). Porphyromonas gingivalis-induced periodontitis promotes neuroinflammation and neuronal loss associated with dysfunction of the brain barrier. Front. Cell. Infect. Microbiol., 15.","DOI":"10.3389\/fcimb.2025.1559182"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"7186","DOI":"10.1002\/jcp.27472","article-title":"Dental pulp stem cells senescence and regenerative potential relationship","volume":"234","author":"Iezzi","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.joen.2023.12.009","article-title":"Senescence on Dental Pulp Cells: Effects on Morphology, Migration, Proliferation, and Immune Response","volume":"50","author":"Martins","year":"2024","journal-title":"J. Endod."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.joen.2012.10.031","article-title":"Aging of In Vitro Pulp Illustrates Change of Inflammation and Dentinogenesis","volume":"39","author":"Lee","year":"2013","journal-title":"J. Endod."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"117464","DOI":"10.1016\/j.bone.2025.117464","article-title":"Klotho senses mechanical stimuli and modulates tension-induced osteogenesis","volume":"195","author":"Men","year":"2025","journal-title":"Bone"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1146\/annurev-pathol-011110-130203","article-title":"Disorders of bone remodeling","volume":"6","author":"Feng","year":"2011","journal-title":"Annu. Rev. Pathol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s13287-016-0300-9","article-title":"Aging, inflammation, stem cells, and bone healing","volume":"7","author":"Gibon","year":"2016","journal-title":"Stem Cell Res. Ther."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1111\/jcpe.12528","article-title":"Bone biology-related gingival transcriptome in ageing and periodontitis in non-human primates","volume":"43","author":"Pandruvada","year":"2016","journal-title":"J. Clin. Periodontol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s40496-018-0202-2","article-title":"Age and Periodontal Health\u2014Immunological View","volume":"5","author":"Ebersole","year":"2018","journal-title":"Curr. Oral. Health Rep."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1177\/1759720X11430858","article-title":"Aging and bone loss: New insights for the clinician","volume":"4","author":"Demontiero","year":"2012","journal-title":"Ther. Adv. Musculoskelet. Dis."},{"key":"ref_132","first-page":"444","article-title":"Senolytic effects on dental pulp stem cell\u2019s proliferation and differentiation during long-term expansion","volume":"59","author":"Wang","year":"2024","journal-title":"Zhonghua Kou Qiang Yi Xue Za Zhi"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"104819","DOI":"10.1016\/j.archoralbio.2020.104819","article-title":"Effects of hydrogen peroxide, doxorubicin and ultraviolet irradiation on senescence of human dental pulp stem cells","volume":"117","author":"Yaghoobi","year":"2020","journal-title":"Arch. Oral. Biol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s13287-021-02209-9","article-title":"Differential SOD2 and GSTZ1 profiles contribute to contrasting dental pulp stem cell susceptibilities to oxidative damage and premature senescence","volume":"12","author":"Alaidaroos","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"119921","DOI":"10.1016\/j.bbamcr.2025.119921","article-title":"Senolytic elimination of senescent cells improved periodontal ligament stem cell-based bone regeneration partially through inhibiting YAP","volume":"1872","author":"Jia","year":"2025","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1146\/annurev-physiol-030212-183653","article-title":"Aging, cellular senescence, and cancer","volume":"75","author":"Campisi","year":"2013","journal-title":"Annu. Rev. Physiol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/nrc2772","article-title":"Senescence in tumours: Evidence from mice and humans","volume":"10","author":"Collado","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1186\/s12943-024-02096-7","article-title":"Cellular senescence and SASP in tumor progression and therapeutic opportunities","volume":"23","author":"Dong","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"29047","DOI":"10.18632\/oncotarget.25540","article-title":"Oral inflammation promotes oral squamous cell carcinoma invasion","volume":"9","author":"Goertzen","year":"2018","journal-title":"Oncotarget"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"e34","DOI":"10.1016\/j.oooo.2024.10.249","article-title":"Exploring senescent oral fibroblasts: Implications in oral squamous cell carcinoma and potential pharmacological interventions","volume":"139","author":"Niklander","year":"2025","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"11762","DOI":"10.1038\/ncomms11762","article-title":"Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis","volume":"7","author":"Ruhland","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"e124716","DOI":"10.1172\/jci.insight.124716","article-title":"Targetable mechanisms driving immunoevasion of persistent senescent cells link chemotherapy-resistant cancer to aging","volume":"4","author":"Yannone","year":"2019","journal-title":"JCI Insight"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/s41571-022-00668-4","article-title":"Senescence and cancer\u2014Role and therapeutic opportunities","volume":"19","author":"Schmitt","year":"2022","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Toan, N.K., and Ahn, S.G. (2021). Aging-Related Metabolic Dysfunction in the Salivary Gland: A Review of the Literature. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115835"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.jobcr.2024.02.009","article-title":"Senescence and fibrosis in salivary gland aging and disease","volume":"14","author":"Nelson","year":"2024","journal-title":"J. Oral. Biol. Craniofac Res."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"2142","DOI":"10.1111\/jgs.13652","article-title":"Meta-Analysis of Salivary Flow Rates in Young and Older Adults","volume":"63","author":"Affoo","year":"2015","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.oooo.2022.12.015","article-title":"Xerostomia, reduced salivary flow, and oral burning: Associations from a cross-sectional study","volume":"136","author":"Eldomiaty","year":"2023","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1111\/j.1365-2842.2009.02027.x","article-title":"Oral sensorial complaints, salivary flow rate and mucosal lesions in the institutionalized elderly","volume":"37","author":"Glazar","year":"2010","journal-title":"J. Oral. Rehabil."},{"key":"ref_149","doi-asserted-by":"crossref","unstructured":"Desai, J.P., and Nair, R.U. (2023). Oral Health Factors Related to Rapid Oral Health Deterioration among Older Adults: A Narrative Review. J. Clin. Med., 12.","DOI":"10.3390\/jcm12093202"},{"key":"ref_150","doi-asserted-by":"crossref","unstructured":"Pei, X.M., Zhou, L.X., Tsang, M.W., Tai, W.C., and Wong, S.C. (2024). The Oral Microbial Ecosystem in Age-Related Xerostomia: A Critical Review. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252312815"},{"key":"ref_151","doi-asserted-by":"crossref","unstructured":"Ahmad, M.S., Bhayat, A., Zafar, M.S., and Al-Samadani, K.H. (2017). The Impact of Hyposalivation on Quality of Life (QoL) and Oral Health in the Aging Population of Al Madinah Al Munawarrah. Int. J. Environ. Res. Public Health, 14.","DOI":"10.3390\/ijerph14040445"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"1996","DOI":"10.1038\/s41467-020-15838-0","article-title":"Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity","volume":"11","author":"He","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"7145","DOI":"10.1182\/blood-2011-03-344812","article-title":"BCL2\/BCL-X(L) inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation","volume":"117","author":"Vogler","year":"2011","journal-title":"Blood"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s10266-023-00810-3","article-title":"Examination of age-related changes in the submandibular glands of male mice","volume":"112","author":"Hirai","year":"2024","journal-title":"Odontology"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"e14470","DOI":"10.1111\/acel.14470","article-title":"Cellular Senescence Contributes to the Dysfunction of Tight Junctions in Submandibular Glands of Aging Mice","volume":"24","author":"Chen","year":"2025","journal-title":"Aging Cell"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"3003","DOI":"10.1093\/rheumatology\/keaa012","article-title":"Progenitor cell niche senescence reflects pathology of the parotid salivary gland in primary Sj\u00f6gren\u2019s syndrome","volume":"59","author":"Wang","year":"2020","journal-title":"Rheumatology"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1002\/art.40659","article-title":"Salivary Gland Stem Cells Age Prematurely in Primary Sj\u00f6gren\u2019s Syndrome","volume":"71","author":"Pringle","year":"2019","journal-title":"Arthritis Rheumatol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"40","DOI":"10.3164\/jcbn.16-79","article-title":"Relationship between hyposalivation and oxidative stress in aging mice","volume":"61","author":"Yamauchi","year":"2017","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/nature10600","article-title":"Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders","volume":"479","author":"Baker","year":"2011","journal-title":"Nature"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1007\/s00432-013-1488-z","article-title":"The development of dasatinib as a treatment for chronic myeloid leukemia (CML): From initial studies to application in newly diagnosed patients","volume":"139","author":"Hochhaus","year":"2013","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"773","DOI":"10.2147\/DDDT.S80207","article-title":"The role of dasatinib in the management of chronic myeloid leukemia","volume":"9","author":"Chen","year":"2015","journal-title":"Drug Des. Devel Ther."},{"key":"ref_162","doi-asserted-by":"crossref","unstructured":"Jazvin\u0161\u0107ak Jembrek, M., Or\u0161oli\u0107, N., Mandi\u0107, L., Sad\u017eak, A., and \u0160egota, S. (2021). Anti-Oxidative, Anti-Inflammatory and Anti-Apoptotic Effects of Flavonols: Targeting Nrf2, NF-\u03baB and p53 Pathways in Neurodegeneration. Antioxidants, 10.","DOI":"10.3390\/antiox10101628"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"11255","DOI":"10.1038\/s41598-018-29308-7","article-title":"Flavonoids inhibit cell proliferation and induce apoptosis and autophagy through downregulation of PI3K\u03b3 mediated PI3K\/AKT\/mTOR\/p70S6K\/ULK signaling pathway in human breast cancer cells","volume":"8","author":"Zhang","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_164","doi-asserted-by":"crossref","unstructured":"Barreca, M.M., Alessandro, R., and Corrado, C. (2023). Effects of Flavonoids on Cancer, Cardiovascular and Neurodegenerative Diseases: Role of NF-\u03baB Signaling Pathway. Int. J. Mol. Sci., 24.","DOI":"10.20944\/preprints202305.0824.v1"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1177\/00220345241299789","article-title":"Dasatinib and Quercetin Limit Gingival Senescence, Inflammation, and Bone Loss","volume":"104","author":"Rattanaprukskul","year":"2025","journal-title":"J. Dent. Res."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1007\/s11357-020-00160-w","article-title":"Age-related changes in the cartilage of the temporomandibular joint","volume":"42","author":"Chen","year":"2020","journal-title":"Geroscience"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"3240","DOI":"10.1002\/art.10690","article-title":"Expression of matrix metalloproteinases in articular cartilage of temporomandibular and knee joints of mice during growth, maturation, and aging","volume":"46","author":"Gepstein","year":"2002","journal-title":"Arthritis Rheum."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"e13394","DOI":"10.1111\/acel.13394","article-title":"Senolytics alleviate the degenerative disorders of temporomandibular joint in old age","volume":"20","author":"Zhou","year":"2021","journal-title":"Aging Cell"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.1111\/odi.15291","article-title":"Dasatinib and Quercetin Mitigate Age-Related Alveolar Bone Inflammaging and Neutrophil Infiltration","volume":"31","author":"Tang","year":"2025","journal-title":"Oral Dis."},{"key":"ref_170","doi-asserted-by":"crossref","unstructured":"Laky, M., Arslan, M., Zhu, X., Rausch-Fan, X., Moritz, A., Sculean, A., Laky, B., Ramseier, C.A., St\u00e4hli, A., and Eick, S. (2024). Quercetin in the Prevention of Induced Periodontal Disease in Animal Models: A Systematic Review and Meta-Analysis. Nutrients, 16.","DOI":"10.3390\/nu16050735"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1111\/joim.13141","article-title":"Senolytic drugs: From discovery to translation","volume":"288","author":"Kirkland","year":"2020","journal-title":"J. Intern. Med."},{"key":"ref_172","doi-asserted-by":"crossref","unstructured":"Torrance, B.L., Cadar, A.N., Martin, D.E., Panier, H.A., Lorenzo, E.C., Bartley, J.M., Xu, M., and Haynes, L. (2023). Senolytic treatment with dasatinib and quercetin does not improve overall influenza responses in aged mice. Front. Aging, 4.","DOI":"10.3389\/fragi.2023.1212750"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1093\/gerona\/glab002","article-title":"Senolytic Combination of Dasatinib and Quercetin Alleviates Intestinal Senescence and Inflammation and Modulates the Gut Microbiome in Aged Mice","volume":"76","author":"Saccon","year":"2021","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_174","doi-asserted-by":"crossref","unstructured":"Amato, M., Polizzi, A., Viglianisi, G., Leonforte, F., Mascitti, M., and Isola, G. (2025). Impact of Periodontitis and Oral Dysbiosis Metabolites in the Modulation of Accelerating Ageing and Human Senescence. Metabolites, 15.","DOI":"10.3390\/metabo15010035"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.eng.2025.07.015","article-title":"Anti-Senescent Biomaterials for Breaking Intervertebral Disc Degeneration","volume":"53","author":"Ding","year":"2025","journal-title":"Engineering"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"101204","DOI":"10.1016\/j.jddst.2019.101204","article-title":"Production of dasatinib encapsulated spray-dried poly (lactic-co-glycolic acid) particles","volume":"53","author":"Chauhan","year":"2019","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"10556","DOI":"10.1002\/anie.201204663","article-title":"Targeted cargo delivery in senescent cells using capped mesoporous silica nanoparticles","volume":"51","author":"Agostini","year":"2012","journal-title":"Angew. Chem.-Int. Ed."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"103027","DOI":"10.1016\/j.arr.2026.103027","article-title":"Proteolysis-targeting chimera (PROTAC): A promising senolytic strategy","volume":"115","author":"Fan","year":"2026","journal-title":"Ageing Res. Rev."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"e54318","DOI":"10.7554\/eLife.54318","article-title":"Rapamycin rejuvenates oral health in aging mice","volume":"9","author":"An","year":"2020","journal-title":"Elife"},{"key":"ref_180","doi-asserted-by":"crossref","unstructured":"Saliev, T., and Singh, P.B. (2025). Targeting Senescence: A Review of Senolytics and Senomorphics in Anti-Aging Interventions. Biomolecules, 15.","DOI":"10.3390\/biom15060860"},{"key":"ref_181","doi-asserted-by":"crossref","unstructured":"Joshi, V.M., Gururaj, S.B., Thumbigere-Math, V., Kugaji, M.S., and Kandaswamy, E. (2025). Rapamycin\u2019s Role in Periodontal Health and Therapeutics: A Scoping Review. JDR Clin. Transl. Res., 23800844251366967.","DOI":"10.1177\/23800844251366967"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"114517","DOI":"10.1016\/j.intimp.2025.114517","article-title":"Rapamycin ameliorates senescence of periodontal ligament stem cells and promotes their osteogenesis via the PI3K\/AKT pathway","volume":"153","author":"Zheng","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.job.2024.08.004","article-title":"Invasion of human dental pulp fibroblasts by Porphyromonas gingivalis leads to autophagy via the phosphoinositide 3-kinase\/Akt\/mammalian target of rapamycin signaling pathway","volume":"66","author":"Feng","year":"2024","journal-title":"J. Oral. Biosci."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"6292630","DOI":"10.1155\/2017\/6292630","article-title":"mTOR Inhibition Rejuvenates the Aging Gingival Fibroblasts through Alleviating Oxidative Stress","volume":"2017","author":"Xia","year":"2017","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1089\/scd.2009.0147","article-title":"Rapamycin promotes the osteoblastic differentiation of human embryonic stem cells by blocking the mTOR pathway and stimulating the BMP\/Smad pathway","volume":"19","author":"Lee","year":"2010","journal-title":"Stem Cells Dev."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"4035306","DOI":"10.1155\/2020\/4035306","article-title":"Rapamycin-Induced Autophagy Promotes the Chondrogenic Differentiation of Synovium-Derived Mesenchymal Stem Cells in the Temporomandibular Joint in Response to IL-1\u03b2","volume":"2020","author":"Liu","year":"2020","journal-title":"Biomed. Res. Int."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1111\/j.1600-0765.2007.01071.x","article-title":"Thrombin induces osteoprotegerin synthesis via phosphatidylinositol 3\u2032-kinase\/mammalian target of rapamycin pathway in human periodontal ligament cells","volume":"43","author":"Arayatrakoollikit","year":"2008","journal-title":"J. Periodontal Res."},{"key":"ref_188","doi-asserted-by":"crossref","unstructured":"Blawat, K., Mayr, A., Hardt, M., Kirschneck, C., Nokhbehsaim, M., Behl, C., Deschner, J., J\u00e4ger, A., and Memmert, S. (2020). Regulation of Autophagic Signaling by Mechanical Loading and Inflammation in Human PDL Fibroblasts. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249446"},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1038\/s41598-020-80275-4","article-title":"Autophagy facilitates type I collagen synthesis in periodontal ligament cells","volume":"11","author":"Nakamura","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1016\/j.transproceed.2007.04.013","article-title":"Effect of rapamycin on wound healing: An experimental study","volume":"39","author":"Ekici","year":"2007","journal-title":"Transplant. Proc."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1172\/JCI95149","article-title":"Strategies targeting cellular senescence","volume":"128","author":"Ovadya","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"328","DOI":"10.18632\/aging.100897","article-title":"NKG2D ligands mediate immunosurveillance of senescent cells","volume":"8","author":"Sagiv","year":"2016","journal-title":"Aging"},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"e202207097","DOI":"10.1083\/jcb.202207097","article-title":"Senescent cells suppress macrophage-mediated corpse removal via upregulation of the CD47-QPCT\/L axis","volume":"222","author":"Schloesser","year":"2023","journal-title":"J. Cell Biol."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s10522-019-09838-x","article-title":"Metformin prevents against oxidative stress-induced senescence in human periodontal ligament cells","volume":"21","author":"Kuang","year":"2020","journal-title":"Biogerontology"},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/s11357-017-9994-6","article-title":"Rapamycin treatment attenuates age-associated periodontitis in mice","volume":"39","author":"An","year":"2017","journal-title":"Geroscience"},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/1423-0127-17-64","article-title":"Overexpression of hTERT increases stem-like properties and decreases spontaneous differentiation in human mesenchymal stem cell lines","volume":"17","author":"Tsai","year":"2010","journal-title":"J. Biomed. Sci."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.stem.2020.07.010","article-title":"A Fresh Approach to Targeting Aging Cells: CAR-T Cells Enhance Senolytic Specificity","volume":"27","author":"Li","year":"2020","journal-title":"Cell Stem Cell"},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1038\/s43587-023-00560-5","article-title":"Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction","volume":"4","author":"Amor","year":"2024","journal-title":"Nat. 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