{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T02:52:27Z","timestamp":1777949547615,"version":"3.51.4"},"reference-count":50,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T00:00:00Z","timestamp":1777680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"NIH\/NIDCR","doi-asserted-by":"publisher","award":["R01 DE030646"],"award-info":[{"award-number":["R01 DE030646"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"NIH\/NIDCR","doi-asserted-by":"publisher","award":["R21 DE034091"],"award-info":[{"award-number":["R21 DE034091"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"NIH\/NIDCR","doi-asserted-by":"publisher","award":["R03 DE028033"],"award-info":[{"award-number":["R03 DE028033"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"NIH\/NIDCR","doi-asserted-by":"publisher","award":["R56 DE023838"],"award-info":[{"award-number":["R56 DE023838"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"NIH\/NIDCR","doi-asserted-by":"publisher","award":["R21 DE031058"],"award-info":[{"award-number":["R21 DE031058"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"NIH\/NIAID","doi-asserted-by":"publisher","award":["R03 AI142273"],"award-info":[{"award-number":["R03 AI142273"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Intermittent fasting confers protection in diverse diseases through various mechanisms, including the clearance of senescent and pathogenic cells, modulation of tissue inflammation and enhancement of stem\/progenitor cell niche and functionality. Our previous study demonstrated the beneficial impact of alternate-day fasting (ADF) on xerostomia and sialadenitis, along with an improvement in salivary gland ductal compartments, where salivary gland progenitor cells reside, in non-obese diabetic mice, a spontaneous model of Sj\u00f6gren\u2019s syndrome (SS). In the present study, we induced SS-associated hyposalivation in KRT5CreERT2; R26tdTomato lineage tracing mice by immunizing them with submandibular gland proteins from wild-type C57BL\/6 mice. ADF alleviated salivary gland hypofunction, which was accompanied by decreased expression of the senescent cell marker p16INK4a, reduced protein levels of anti-apoptotic proteins BCL-2, BCL-XL, and MCL-1, and attenuated NLRP3 inflammasome activity in the submandibular glands, particularly within the ductal compartments, of this inducible model. Furthermore, immunofluorescence staining of submandibular gland sections revealed the expression of the acinar cell marker aquaporin 5 in a small subset of Keratin 5+ cells in 2 of 9 mice that were subjected to ADF, whereas no such cells were detected in the control mice. Taken together, these findings indicate that ADF favorably modulates the salivary gland progenitor cell niche, potentially by promoting apoptosis-mediated senescent cell clearance, suppressing NLRP3 inflammasome signaling, and promoting Keratin 5+ progenitor cell-derived acinar cell replenishment, thereby contributing to the structural and functional restoration of damaged salivary glands in autoimmune exocrinopathy.<\/jats:p>","DOI":"10.3390\/ijms27094080","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T01:12:09Z","timestamp":1777857129000},"page":"4080","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Impact of Alternate-Day Fasting on the Salivary Gland Ductal Compartments and the Differentiation Potential of Keratin 5+ Salivary Gland Progenitor Cells in an Induced Mouse Model of Sj\u00f6gren\u2019s-like Hyposalivation"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3282-3055","authenticated-orcid":false,"given":"Dongfang","family":"Li","sequence":"first","affiliation":[{"name":"The ADA Forsyth Institute, 100 Chestnut Street, Somerville, MA 02143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0673-3400","authenticated-orcid":false,"given":"Shoko","family":"Onodera","sequence":"additional","affiliation":[{"name":"The ADA Forsyth Institute, 100 Chestnut Street, Somerville, MA 02143, USA"},{"name":"Department of Biochemistry, Tokyo Dental College, Tokyo 101-0061, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5818-0564","authenticated-orcid":false,"given":"Qing","family":"Yu","sequence":"additional","affiliation":[{"name":"The ADA Forsyth Institute, 100 Chestnut Street, Somerville, MA 02143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8979-1353","authenticated-orcid":false,"given":"Jing","family":"Zhou","sequence":"additional","affiliation":[{"name":"The ADA Forsyth Institute, 100 Chestnut Street, Somerville, MA 02143, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1196\/annals.1384.003","article-title":"Autoimmune diseases and Sjogren\u2019s syndrome: An autoimmune exocrinopathy","volume":"1098","author":"Fox","year":"2007","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_2","first-page":"689","article-title":"Sjogren\u2019s syndrome","volume":"30","author":"Rhodus","year":"1999","journal-title":"Quintessence Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/nrrheum.2010.118","article-title":"Pathogenetic mechanisms in the initiation and perpetuation of Sjogren\u2019s syndrome","volume":"6","author":"Voulgarelis","year":"2010","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_4","first-page":"247","article-title":"The epidemiology of Sjogren\u2019s syndrome","volume":"6","author":"Patel","year":"2014","journal-title":"Clin. Epidemiol."},{"key":"ref_5","first-page":"9","article-title":"T Cell-Associated Cytokines in the Pathogenesis of Sjogren\u2019s Syndrome","volume":"S1","author":"Jin","year":"2013","journal-title":"J. Clin. Cell. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/s00005-009-0002-4","article-title":"Sjogren\u2019s syndrome: An old tale with a new twist","volume":"57","author":"Lee","year":"2009","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/sj.bdj.2012.890","article-title":"Sjogren\u2019s syndrome\u2014An update for dental practitioners","volume":"213","author":"Carr","year":"2012","journal-title":"Br. Dent. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.stemcr.2015.11.009","article-title":"Long-Term In Vitro Expansion of Salivary Gland Stem Cells Driven by Wnt Signals","volume":"6","author":"Maimets","year":"2016","journal-title":"Stem Cell Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1016\/j.celrep.2018.07.016","article-title":"Limited Regeneration of Adult Salivary Glands after Severe Injury Involves Cellular Plasticity","volume":"24","author":"Weng","year":"2018","journal-title":"Cell Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1016\/j.stemcr.2014.09.015","article-title":"Purification and ex vivo expansion of fully functional salivary gland stem cells","volume":"3","author":"Nanduri","year":"2014","journal-title":"Stem Cell Rep."},{"key":"ref_11","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 Sjogren\u2019s syndrome","volume":"59","author":"Wang","year":"2020","journal-title":"Rheumatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.arr.2016.10.005","article-title":"Impact of intermittent fasting on health and disease processes","volume":"39","author":"Mattson","year":"2017","journal-title":"Ageing Res. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.cmet.2013.12.008","article-title":"Fasting: Molecular mechanisms and clinical applications","volume":"19","author":"Longo","year":"2014","journal-title":"Cell Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1093\/ajcn\/86.1.7","article-title":"Alternate-day fasting and chronic disease prevention: A review of human and animal trials","volume":"86","author":"Varady","year":"2007","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1056\/NEJMra1905136","article-title":"Effects of Intermittent Fasting on Health, Aging, and Disease","volume":"381","author":"Mattson","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3985089","DOI":"10.1155\/2020\/3985089","article-title":"Fasting Induces Hepatocellular Carcinoma Cell Apoptosis by Inhibiting SET8 Expression","volume":"2020","author":"Qi","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2136","DOI":"10.1016\/j.celrep.2016.05.009","article-title":"A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms","volume":"15","author":"Choi","year":"2016","journal-title":"Cell Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.arr.2018.08.004","article-title":"The effect of fasting or calorie restriction on autophagy induction: A review of the literature","volume":"47","author":"Bagherniya","year":"2018","journal-title":"Ageing Res. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Li, D., Onodera, S., Deng, S., Alnujaydi, B., Yu, Q., and Zhou, J. (2022). Alternate-Day Fasting Ameliorates Newly Established Sjogren\u2019s Syndrome-like Sialadenitis in Non-Obese Diabetic Mice. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232213791"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"119817","DOI":"10.1016\/j.bbamcr.2024.119817","article-title":"The impact of alternate-day fasting on the salivary gland stem cell compartments in non-obese diabetic mice with newly established Sjogren\u2019s syndrome","volume":"1871","author":"Li","year":"2024","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.4049\/jimmunol.1801051","article-title":"Increased GITRL Impairs the Function of Myeloid-Derived Suppressor Cells and Exacerbates Primary Sjogren Syndrome","volume":"202","author":"Tian","year":"2019","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1093\/intimm\/dxr066","article-title":"An autoimmunized mouse model recapitulates key features in the pathogenesis of Sjogren\u2019s syndrome","volume":"23","author":"Lin","year":"2011","journal-title":"Int. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1136\/annrheumdis-2013-204584","article-title":"Th17 cells play a critical role in the development of experimental Sjogren\u2019s syndrome","volume":"74","author":"Lin","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/nm.4010","article-title":"Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice","volume":"22","author":"Chang","year":"2016","journal-title":"Nat. Med."},{"key":"ref_25","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_26","doi-asserted-by":"crossref","unstructured":"Kelley, N., Jeltema, D., Duan, Y., and He, Y. (2019). The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133328"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kumari, R., and Jat, P. (2021). Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.645593"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zhang, L., Pitcher, L.E., Yousefzadeh, M.J., Niedernhofer, L.J., Robbins, P.D., and Zhu, Y. (2022). Cellular senescence: A key therapeutic target in aging and diseases. J. Clin. Invest., 132.","DOI":"10.1172\/JCI158450"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1093\/lifemedi\/lnac030","article-title":"Targeting senescent cells for a healthier longevity: The roadmap for an era of global aging","volume":"1","author":"Sun","year":"2022","journal-title":"Life Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"111548","DOI":"10.1016\/j.mad.2021.111548","article-title":"Impact of Senescent Cell Subtypes on Tissue Dysfunction and Repair: Importance and Research Questions","volume":"198","author":"Tripathi","year":"2021","journal-title":"Mech. Ageing Dev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1038\/s41591-022-01923-y","article-title":"Cellular senescence and senolytics: The path to the clinic","volume":"28","author":"Chaib","year":"2022","journal-title":"Nat. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1111\/joim.12115","article-title":"The P2X7 receptor-inflammasome complex has a role in modulating the inflammatory response in primary Sjogren\u2019s syndrome","volume":"274","author":"Baldini","year":"2013","journal-title":"J. Intern. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"16626","DOI":"10.1074\/jbc.M117.790741","article-title":"P2X7 receptor antagonism prevents IL-1beta release from salivary epithelial cells and reduces inflammation in a mouse model of autoimmune exocrinopathy","volume":"292","author":"Khalafalla","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1093\/rheumatology\/kew013","article-title":"Sjogren\u2019s syndrome patients with ectopic germinal centers present with a distinct salivary proteome","volume":"55","author":"Delaleu","year":"2016","journal-title":"Rheumatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1517\/14728222.2013.754427","article-title":"Targeting IL-1 in Sjogren\u2019s syndrome","volume":"17","author":"Yamada","year":"2013","journal-title":"Expert. Opin. Ther. Targets"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"C790","DOI":"10.1152\/ajpcell.00072.2012","article-title":"P2X7 receptor activation induces inflammatory responses in salivary gland epithelium","volume":"303","author":"Woods","year":"2012","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1111\/imm.13605","article-title":"Inhibition of NLRP3 inflammasome activity by MCC950 leads to exacerbation of Sj\u00f6gren\u2019s syndrome pathologies in non-obese diabetic mice","volume":"168","author":"Zhou","year":"2023","journal-title":"Immunology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5299","DOI":"10.21037\/apm-20-2410","article-title":"Intermittent fasting therapy promotes insulin sensitivity by inhibiting NLRP3 inflammasome in rat model","volume":"10","author":"Liang","year":"2021","journal-title":"Ann. Palliat. Med."},{"key":"ref_39","first-page":"4063562","article-title":"NLRP3 Inflammasome and Inflammatory Diseases","volume":"2020","author":"Wang","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"110542","DOI":"10.1016\/j.biopha.2020.110542","article-title":"Role of the NLRP3 inflammasome in autoimmune diseases","volume":"130","author":"Li","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s13619-025-00221-5","article-title":"Salivary gland stem\/progenitor cells: Advancing from basic science to clinical applications","volume":"14","author":"Langthasa","year":"2025","journal-title":"Cell Regen."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2217","DOI":"10.1021\/acsbiomaterials.6b00419","article-title":"Tuning Hydrogel Properties to Promote the Assembly of Salivary Gland Spheroids in 3D","volume":"2","author":"Ozdemir","year":"2016","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1002\/term.2908","article-title":"Cell culture of differentiated human salivary epithelial cells in a serum-free and scalable suspension system: The salivary functional units model","volume":"13","author":"Seo","year":"2019","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s40778-017-0072-x","article-title":"Dietary Regulation of Adult Stem Cells","volume":"3","author":"Mana","year":"2017","journal-title":"Curr. Stem Cell Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1016\/j.stem.2014.04.014","article-title":"Prolonged fasting reduces IGF-1\/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression","volume":"14","author":"Cheng","year":"2014","journal-title":"Cell Stem Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1385\/JMN:15:2:99","article-title":"Dietary restriction increases the number of newly generated neural cells, and induces BDNF expression, in the dentate gyrus of rats","volume":"15","author":"Lee","year":"2000","journal-title":"J. Mol. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1046\/j.0022-3042.2001.00747.x","article-title":"Dietary restriction enhances neurotrophin expression and neurogenesis in the hippocampus of adult mice","volume":"80","author":"Lee","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"166302","DOI":"10.1016\/j.bbadis.2021.166302","article-title":"Plasmacytoid dendritic cells promote the pathogenesis of Sjogren\u2019s syndrome","volume":"1868","author":"Zhou","year":"2022","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Zhou, J., Onodera, S., Hu, Y., and Yu, Q. (2022). Interleukin-22 Exerts Detrimental Effects on Salivary Gland Integrity and Function. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232112997"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"165605","DOI":"10.1016\/j.bbadis.2019.165605","article-title":"Agonist-induced 4-1BB activation prevents the development of Sj\u00f6gren\u2019s syndrome-like sialadenitis in non-obese diabetic mice","volume":"1866","author":"Zhou","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/4080\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T01:13:10Z","timestamp":1777857190000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/4080"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,2]]},"references-count":50,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27094080"],"URL":"https:\/\/doi.org\/10.3390\/ijms27094080","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,2]]}}}