{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T05:06:11Z","timestamp":1789189571520,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["#25-25-00484"],"award-info":[{"award-number":["#25-25-00484"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"award":["#25-25-00484"],"award-info":[{"award-number":["#25-25-00484"]}],"id":[{"id":"https:\/\/ror.org\/03y2gwe85","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cellular senescence of adipose tissue-derived mesenchymal stromal cells (AD-MSCs) is associated with chronic low-grade inflammation, metabolic dysfunction, and impaired adipogenesis contributing to the development of obesity, insulin resistance, and the progression of age-associated diseases. The aim of this study was to develop a model of cellular aging based on AD-MSCs to study the senolytic efficacy of the natural fisetin preparation for the subsequent development of geroprotective therapeutic strategies. The senescent markers SA-\u03b2-gal, SASP factors, and cell cycle arrest markers p16, p21, and p53 were assessed in models of replicative and stress-induced aging of AD-MSCs. H2O2 was identified as the most effective inducer of AD-MSC cellular senescence in comparison with LPS. It has been shown in the model of H2O2-induced senescence of AD-MSCs that the proportion of SA-\u03b2-gal+ cells was 2.0 (0.7)% in non-stimulated AD-MSCs, 81.7 (12.1)% in H2O2-stimulated AD-MSCs, and 19.1 (5.2)% and 13.0 (3.2)% after short-term (24 h) and long-term (7 days) fisetin treatment, respectively, indicating that fisetin treatment was associated with a lower proportion of SA-\u03b2-gal+ cells. Fisetin treatment resulted in a statistically significant decrease in the secretion of MCP-1, especially during long-term incubation. IL-1\u03b2 showed a significant decrease after 7 days of fisetin treatment compared to H2O2, but the effect at 24 h was only significant in the group of 7 days of fisetin treatment. Fisetin treatment was also associated with higher p53 and p21 concentrations. Thus, in the present study, a model of H2O2-induced cellular senescence of AD-MSCs was developed, which can be used to evaluate the geroprotective potential of senotherapeutic preparations; fisetin warrants further evaluation as a potential senotherapeutic agent in this model.<\/jats:p>","DOI":"10.3390\/cells15181634","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T16:43:16Z","timestamp":1788972196000},"page":"1634","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Development of Cellular Aging Models Based on AD-MSCs"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9646-8091","authenticated-orcid":false,"given":"Natalia V.","family":"Elizova","sequence":"first","affiliation":[{"name":"Petrovsky National Research Centre of Surgery, 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan V.","family":"Zhivodernikov","sequence":"additional","affiliation":[{"name":"Petrovsky National Research Centre of Surgery, 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2220-9695","authenticated-orcid":false,"given":"Vyacheslav S.","family":"Vasilyev","sequence":"additional","affiliation":[{"name":"Institute of Plastic Surgery and Cosmetology, 105066 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5188-1890","authenticated-orcid":false,"given":"Yaroslav D.","family":"Tolkachev","sequence":"additional","affiliation":[{"name":"Petrovsky National Research Centre of Surgery, 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3781-6340","authenticated-orcid":false,"given":"Yuliya V.","family":"Markina","sequence":"additional","affiliation":[{"name":"Petrovsky National Research Centre of Surgery, 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6649-7924","authenticated-orcid":false,"given":"Alexander M.","family":"Markin","sequence":"additional","affiliation":[{"name":"Petrovsky National Research Centre of Surgery, 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2899-9202","authenticated-orcid":false,"given":"Tatiana V.","family":"Kirichenko","sequence":"additional","affiliation":[{"name":"Petrovsky National Research Centre of Surgery, 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Sebaa, R. (2026). Exploring Adipose Tissue Complexity Through Omics Approaches: Implications for Health and Disease. Cells, 15.","DOI":"10.3390\/cells15050427"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Park, S., and Shimokawa, I. (2024). Influence of Adipokines on Metabolic Dysfunction and Aging. Biomedicines, 12.","DOI":"10.3390\/biomedicines12040873"},{"key":"ref_3","first-page":"12","article-title":"Finding a Link between Obesity and Senescence: A Systematic Review and Meta-Analysis","volume":"53","author":"Widjaja","year":"2024","journal-title":"Iran. J. Public Health"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Conley, S.M., Hickson, L.J., Kellogg, T.A., McKenzie, T., Heimbach, J.K., Taner, T., Tang, H., Jordan, K.L., Saadiq, I.M., and Woollard, J.R. (2020). Human Obesity Induces Dysfunction and Early Senescence in Adipose Tissue-Derived Mesenchymal Stromal\/Stem Cells. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00197"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"111988","DOI":"10.1016\/j.mad.2024.111988","article-title":"Adipose tissue senescence: Biological changes, hallmarks and therapeutic approaches","volume":"222","author":"Zhang","year":"2024","journal-title":"Mech. Ageing Dev."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Voynova, E., Kulebyakin, K., Grigorieva, O., Novoseletskaya, E., Basalova, N., Alexandrushkina, N., Arbatskiy, M., Vigovskiy, M., Sorokina, A., and Zinoveva, A. (2022). Declined adipogenic potential of senescent MSCs due to shift in insulin signaling and altered exosome cargo. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.1050489"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.advms.2025.10.002","article-title":"Enhancing the clinical potential: Quality assessment of adipose tissue-derived Mesenchymal Stem\/Stromal Cells for therapeutic use","volume":"70","author":"Rytel","year":"2025","journal-title":"Adv. Med. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s12265-022-10279-0","article-title":"Human Obesity Attenuates Cardioprotection Conferred by Adipose Tissue-Derived Mesenchymal Stem\/Stromal Cells","volume":"16","author":"Yu","year":"2023","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Dangerfield, J.A., and Metzner, C. (2026). Collecting Eggs, Not Killing Chickens: Why Stem Cell Secretome and Exosomes Are Redefining Regenerative Medicine for Healthspan Extension. Biomedicines, 14.","DOI":"10.3390\/biomedicines14040854"},{"key":"ref_10","first-page":"2554","article-title":"Targeting Cellular Senescence in Aging and Age-Related Diseases: Challenges, Considerations, and the Emerging Role of Senolytic and Senomorphic Therapies","volume":"15","author":"Zheng","year":"2024","journal-title":"Aging Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100102","DOI":"10.1016\/j.mocell.2024.100102","article-title":"Brief guide to senescence assays using cultured mammalian cells","volume":"47","author":"Kang","year":"2024","journal-title":"Mol. Cells"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"100113","DOI":"10.1016\/j.mocell.2024.100113","article-title":"The role of p21 in cellular senescence and aging-related diseases","volume":"47","author":"Yan","year":"2024","journal-title":"Mol. Cells"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/7651_2024_580","article-title":"Mesenchymal Stromal Cell (MSC) Isolation and Induction of Acute and Replicative Senescence","volume":"2960","author":"Samiminemati","year":"2025","journal-title":"Methods Mol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s11658-022-00366-0","article-title":"Aging of mesenchymal stem cell: Machinery, markers, and strategies of fighting","volume":"27","author":"Safi","year":"2022","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Kashyap, D., Garg, V.K., Tuli, H.S., Yerer, M.B., Sak, K., Sharma, A.K., Kumar, M., Aggarwal, V., and Sandhu, S.S. (2019). Fisetin and Quercetin: Promising Flavonoids with Chemopreventive Potential. Biomolecules, 9.","DOI":"10.3390\/biom9050174"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1080\/14653240600855905","article-title":"Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement","volume":"8","author":"Dominici","year":"2006","journal-title":"Cytotherapy"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Suzuki, K., Susaki, E.A., and Nagaoka, I. (2022). Lipopolysaccharides and Cellular Senescence: Involvement in Atherosclerosis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911148"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Veronesi, F., Contartese, D., Di Sarno, L., Borsari, V., Fini, M., and Giavaresi, G. (2023). In Vitro Models of Cell Senescence: A Systematic Review on Musculoskeletal Tissues and Cells. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242115617"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e14446","DOI":"10.1111\/acel.14446","article-title":"Nuclear respiratory factor-1 (NRF1) induction as a powerful strategy to deter mitochondrial dysfunction and senescence in mesenchymal stem cells","volume":"24","author":"Lee","year":"2025","journal-title":"Aging Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s41065-026-00646-1","article-title":"Ginsenoside Rg1 delays the senescence of adipose-derived stem cells: Network pharmacology and experimental validation","volume":"163","author":"Fang","year":"2026","journal-title":"Hereditas"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1093\/stmcls\/sxae010","article-title":"S-Adenosyl-l-Methionine Alleviates the Senescence of MSCs Through the PI3K\/AKT\/FOXO3a Signaling Pathway","volume":"42","author":"Shang","year":"2024","journal-title":"Stem Cells"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"101458","DOI":"10.1016\/j.arr.2021.101458","article-title":"A common signature of cellular senescence; does it exist?","volume":"71","author":"Sikora","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"106841","DOI":"10.1016\/j.phrs.2023.106841","article-title":"Role of Hypoxia in Cellular Senescence","volume":"194","author":"Gao","year":"2023","journal-title":"Pharmacol. Res."},{"key":"ref_24","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_25","doi-asserted-by":"crossref","unstructured":"Manu, K.A., Cao, P.H.A., Chai, T.F., Casey, P.J., and Wang, M. (2019). P21cip1\/Waf1 Coordinate Autophagy, Proliferation and Apoptosis in Response to Metabolic Stress. Cancers, 11.","DOI":"10.3390\/cancers11081112"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"338","DOI":"10.52601\/bpr.2023.230032","article-title":"Regulation of Cellular Senescence by Innate Immunity","volume":"9","author":"Hou","year":"2023","journal-title":"Biophys. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/978-1-59745-361-5_3","article-title":"Methods to Detect Biomarkers of Cellular Senescence: The Senescence-Associated Beta-Galactosidase Assay","volume":"371","author":"Itahana","year":"2007","journal-title":"Methods Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1186\/s13287-018-1081-0","article-title":"A PH Probe Inhibits Senescence in Mesenchymal Stem Cells","volume":"9","author":"Wang","year":"2018","journal-title":"Stem Cell Res. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ozdemir, S.A., Faizan, M.I., Kaur, G., Shaikh, S.B., Ul Islam, K., and Rahman, I. (2025). Heterogeneity of Cellular Senescence, Senotyping, and Targeting by Senolytics and Senomorphics in Lung Diseases. Int. J. Mol. Sci., 26.","DOI":"10.20944\/preprints202508.1331.v1"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1002\/ame2.12476","article-title":"A comprehensive view on the fisetin impact on colorectal cancer in animal models: Focusing on cellular and molecular mechanisms","volume":"7","author":"Zamanian","year":"2024","journal-title":"Anim. Models Exp. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"111995","DOI":"10.1016\/j.mad.2024.111995","article-title":"Fisetin as a senotherapeutic agent: Evidence and perspectives for age-related diseases","volume":"222","author":"Tavenier","year":"2024","journal-title":"Mech. Ageing Dev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e14060","DOI":"10.1111\/acel.14060","article-title":"Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence","volume":"23","author":"Mahoney","year":"2024","journal-title":"Aging Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"111591","DOI":"10.1016\/j.mad.2021.111591","article-title":"Strategies for late phase preclinical and early clinical trials of senolytics","volume":"200","author":"Misra","year":"2021","journal-title":"Mech. Ageing Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1093\/stmcls\/sxad036","article-title":"Fisetin Attenuates Cellular Senescence Accumulation During Culture Expansion of Human Adipose-Derived Stem Cells","volume":"41","author":"Mullen","year":"2023","journal-title":"Stem Cells"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ebiom.2018.09.015","article-title":"Fisetin is a senotherapeutic that extends health and lifespan","volume":"36","author":"Yousefzadeh","year":"2018","journal-title":"eBioMedicine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s10522-023-10064-9","article-title":"Fisetin, a potential skin rejuvenation drug that eliminates senescent cells in the dermis","volume":"25","author":"Takaya","year":"2024","journal-title":"Biogerontology"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kirichenko, T.V., Markina, Y.V., Markin, A.M., Vasilyev, V.S., Hua, H., Li, D., Woo, A.Y., Deev, R.V., Eremin, I.I., and Kotenko, K.V. (2025). Functional Features of Senescent Cells and Implications for Therapy. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26115390"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/18\/1634\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T04:13:36Z","timestamp":1789186416000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/18\/1634"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,9]]},"references-count":37,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cells15181634"],"URL":"https:\/\/doi.org\/10.3390\/cells15181634","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,9]]}}}