Aging is characterized by gradual deterioration of organ or tissue function and its ability to maintain homeostasis of the different physiological processes. This leads to the development of structural and functional alterations accompanied by an increased risk for diverse pathologies. Cellular senescence is a controlled biological process that could contribute to the development of many age-related diseases and related metabolic dysfunctions. Two major chronic diseases associated with premature accumulation of senescent cells that impose an enormous burden on global health systems are obesity and type 2 diabetes mellitus with its related complications. The purpose of this review is to highlight the links between aging, obesity, and type 2 diabetes mellitus, focusing on the role of cellular senescence in disease development and progression. Additionally, this review will discuss the potential of targeting cellular senescence as a promising therapeutic strategy for managing these interrelated diseases, therefore offering a novel approach to prevention and treatment.

1st Faculty of Medicine Charles University Prague Prague Czechia

Centre for Experimental Medicine Institute for Clinical and Experimental Medicine Prague Czechia

Department of Biochemistry and Microbiology University of Chemistry and Technology Prague Czechia

Diabetes Centre Institute for Clinical and Experimental Medicine Prague Czechia

Institute of Biotechnology Czech Academy of Sciences Prague Czechia

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University and General University Hospital Prague Czechia

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Abdellatif M., Trummer-Herbst V., Heberle A. M., Humnig A., Pendl T., Durand S., et al. (2022). Fine-tuning cardiac insulin-like growth factor 1 receptor signaling to promote health and longevity. Circulation 145 (25), 1853–1866. 10.1161/CIRCULATIONAHA.122.059863 PubMed DOI PMC

Aguayo-Mazzucato C., Andle J., Lee T. B., Jr., Midha A., Talemal L., Chipashvili V., et al. (2019). Acceleration of beta cell aging determines diabetes and senolysis improves disease outcomes. Cell Metab. 30 (1), 129–142. 10.1016/j.cmet.2019.05.006 PubMed DOI PMC

Aguayo-Mazzucato C., van Haaren M., Mruk M., Lee T. B., Jr., Crawford C., Hollister-Lock J., et al. (2017). Beta cell aging markers have heterogeneous distribution and are induced by insulin resistance. Cell Metab. 25 (4), 898–910 e5. 10.1016/j.cmet.2017.03.015 PubMed DOI PMC

Aguiar-Oliveira M. H., Bartke A. (2019). Growth hormone deficiency: health and longevity. Endocr. Rev. 40 (2), 575–601. 10.1210/er.2018-00216 PubMed DOI PMC

Alessio N., Acar M. B., Demirsoy I. H., Squillaro T., Siniscalco D., Di Bernardo G., et al. (2020). Obesity is associated with senescence of mesenchymal stromal cells derived from bone marrow, subcutaneous and visceral fat of young mice. Aging (Albany NY) 12 (13), 12609–12621. 10.18632/aging.103606 PubMed DOI PMC

AlQudah M., Hale T. M., Czubryt M. P. (2020). Targeting the renin-angiotensin-aldosterone system in fibrosis. Matrix Biol. 91-92, 92–108. 10.1016/j.matbio.2020.04.005 PubMed DOI PMC

Alsalem M., Ellaithy A., Bloukh S., Haddad M., Saleh T. (2024). Targeting therapy-induced senescence as a novel strategy to combat chemotherapy-induced peripheral neuropathy. Support Care Cancer 32 (1), 85. 10.1007/s00520-023-08287-0 PubMed DOI

Althunibat O. Y., Al Hroob A. M., Abukhalil M. H., Germoush M. O., Bin-Jumah M., Mahmoud A. M. (2019). Fisetin ameliorates oxidative stress, inflammation and apoptosis in diabetic cardiomyopathy. Life Sci. 221, 83–92. 10.1016/j.lfs.2019.02.017 PubMed DOI

Armstrong G. T., Kawashima T., Leisenring W., Stratton K., Stovall M., Hudson M. M., et al. (2014). Aging and risk of severe, disabling, life-threatening, and fatal events in the childhood cancer survivor study. J. Clin. Oncol. 32 (12), 1218–1227. 10.1200/JCO.2013.51.1055 PubMed DOI PMC

Baker D. J., Petersen R. C. (2018). Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives. J. Clin. Invest 128 (4), 1208–1216. 10.1172/JCI95145 PubMed DOI PMC

Barnes P. J. (2017). Senescence in COPD and its comorbidities. Annu. Rev. Physiol. 79, 517–539. 10.1146/annurev-physiol-022516-034314 PubMed DOI

Barzilai N., Crandall J. P., Kritchevsky S. B., Espeland M. A. (2016). Metformin as a tool to target aging. Cell Metab. 23 (6), 1060–1065. 10.1016/j.cmet.2016.05.011 PubMed DOI PMC

Baur J. A., Pearson K. J., Price N. L., Jamieson H. A., Lerin C., Kalra A., et al. (2006). Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444 (7117), 337–342. 10.1038/nature05354 PubMed DOI PMC

Besancenot R., Chaligne R., Tonetti C., Pasquier F., Marty C., Lecluse Y., et al. (2010). A senescence-like cell-cycle arrest occurs during megakaryocytic maturation: implications for physiological and pathological megakaryocytic proliferation. PLoS Biol. 8 (9), e1000476. 10.1371/journal.pbio.1000476 PubMed DOI PMC

Birch J., Gil J. (2020). Senescence and the SASP: many therapeutic avenues. Genes Dev. 34 (23-24), 1565–1576. 10.1101/gad.343129.120 PubMed DOI PMC

Bodnar A. G., Ouellette M., Frolkis M., Holt S. E., Chiu C. P., Morin G. B., et al. (1998). Extension of life-span by introduction of telomerase into normal human cells. Science 279 (5349), 349–352. 10.1126/science.279.5349.349 PubMed DOI

Bonnet L., Alexandersson I., Baboota R. K., Kroon T., Oscarsson J., Smith U., et al. (2022). Cellular senescence in hepatocytes contributes to metabolic disturbances in NASH. Front. Endocrinol. (Lausanne) 13, 957616. 10.3389/fendo.2022.957616 PubMed DOI PMC

Bringardner B. D., Baran C. P., Eubank T. D., Marsh C. B. (2008). The role of inflammation in the pathogenesis of idiopathic pulmonary fibrosis. Antioxid. Redox Signal 10 (2), 287–301. 10.1089/ars.2007.1897 PubMed DOI PMC

Cao Y., Zeng W., Cui Y., Kong X., Wang M., Yu J., et al. (2018). Increased myocardial extracellular volume assessed by cardiovascular magnetic resonance T1 mapping and its determinants in type 2 diabetes mellitus patients with normal myocardial systolic strain. Cardiovasc Diabetol. 17 (1), 7. 10.1186/s12933-017-0651-2 PubMed DOI PMC

Chen H., Chen H., Liang J., Gu X., Zhou J., Xie C., et al. (2020). TGF-β1/IL-11/MEK/ERK signaling mediates senescence-associated pulmonary fibrosis in a stress-induced premature senescence model of Bmi-1 deficiency. Exp. Mol. Med. 52 (1), 130–151. 10.1038/s12276-019-0371-7 PubMed DOI PMC

Chen P. Y., Qin L., Li G., Wang Z., Dahlman J. E., Malagon-Lopez J., et al. (2019b). Endothelial TGF-beta signalling drives vascular inflammation and atherosclerosis. Nat. Metab. 1 (9), 912–926. 10.1038/s42255-019-0102-3 PubMed DOI PMC

Chen Y. Y., Yu X. Y., Chen L., Vaziri N. D., Ma S. C., Zhao Y. Y. (2019a). Redox signaling in aging kidney and opportunity for therapeutic intervention through natural products. Free Radic. Biol. Med. 141, 141–149. 10.1016/j.freeradbiomed.2019.06.012 PubMed DOI

Coelho M., Oliveira T., Fernandes R. (2013). Biochemistry of adipose tissue: an endocrine organ. Arch. Med. Sci. 9 (2), 191–200. 10.5114/aoms.2013.33181 PubMed DOI PMC

Covarrubias A. J., Kale A., Perrone R., Lopez-Dominguez J. A., Pisco A. O., Kasler H. G., et al. (2020). Senescent cells promote tissue NAD(+) decline during ageing via the activation of CD38(+) macrophages. Nat. Metab. 2 (11), 1265–1283. 10.1038/s42255-020-00305-3 PubMed DOI PMC

Cree L. M., Patel S. K., Pyle A., Lynn S., Turnbull D. M., Chinnery P. F., et al. (2008). Age-related decline in mitochondrial DNA copy number in isolated human pancreatic islets. Diabetologia 51 (8), 1440–1443. 10.1007/s00125-008-1054-4 PubMed DOI

Cristofalo V. J., Lorenzini A., Allen R. G., Torres C., Tresini M. (2004). Replicative senescence: a critical review. Mech. Ageing Dev. 125 (10-11), 827–848. 10.1016/j.mad.2004.07.010 PubMed DOI

Dai D. F., Chiao Y. A., Marcinek D. J., Szeto H. H., Rabinovitch P. S. (2014). Mitochondrial oxidative stress in aging and healthspan. Longev. Heal. 3, 6. 10.1186/2046-2395-3-6 PubMed DOI PMC

Demaria M., Ohtani N., Youssef S. A., Rodier F., Toussaint W., Mitchell J. R., et al. (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31 (6), 722–733. 10.1016/j.devcel.2014.11.012 PubMed DOI PMC

de Oliveira Silva T., Lunardon G., Lino C. A., de Almeida Silva A., Zhang S., Irigoyen M. C. C., et al. (2025). Senescent cell depletion alleviates obesity-related metabolic and cardiac disorders. Mol. Metab. 91, 102065. 10.1016/j.molmet.2024.102065 PubMed DOI PMC

Di Micco R., Krizhanovsky V., Baker D., d'Adda di Fagagna F. (2021). Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat. Rev. Mol. Cell Biol. 22 (2), 75–95. 10.1038/s41580-020-00314-w PubMed DOI PMC

Dong W., Jia C., Li J., Zhou Y., Luo Y., Liu J., et al. (2022). Fisetin attenuates diabetic nephropathy-induced podocyte injury by inhibiting NLRP3 inflammasome. Front. Pharmacol. 13, 783706. 10.3389/fphar.2022.783706 PubMed DOI PMC

Du K., Umbaugh D. S., Liuyang W., Jun J. H., Dutta R. K., Oh S. H., et al. (2025). Targeting senescent hepatocytes for treatment of metabolic dysfunction-associated steatotic liver disease and multi-organ dysfunction. Nat. Commun. 16 (1), 3038. 10.1038/s41467-025-57616-w PubMed DOI PMC

El Assar M., Alvarez-Bustos A., Sosa P., Angulo J., Rodriguez-Manas L. (2022). Effect of physical activity/exercise on oxidative stress and inflammation in muscle and vascular aging. Int. J. Mol. Sci. 23 (15), 8713. 10.3390/ijms23158713 PubMed DOI PMC

Feng X., Wang L., Zhou R., Zhou R., Chen L., Peng H., et al. (2023). Senescent immune cells accumulation promotes brown adipose tissue dysfunction during aging. Nat. Commun. 14 (1), 3208. 10.1038/s41467-023-38842-6 PubMed DOI PMC

Fijany A., Sayadi L. R., Khoshab N., Banyard D. A., Shaterian A., Alexander M., et al. (2019). Mesenchymal stem cell dysfunction in diabetes. Mol. Biol. Rep. 46 (1), 1459–1475. 10.1007/s11033-018-4516-x PubMed DOI

Foretz M., Guigas B., Bertrand L., Pollak M., Viollet B. (2014). Metformin: from mechanisms of action to therapies. Cell Metab. 20 (6), 953–966. 10.1016/j.cmet.2014.09.018 PubMed DOI

Foretz M., Viollet B. (2015). Therapy: metformin takes a new route to clinical efficacy. Nat. Rev. Endocrinol. 11 (7), 390–392. 10.1038/nrendo.2015.85 PubMed DOI PMC

Fox C. S., Massaro J. M., Hoffmann U., Pou K. M., Maurovich-Horvat P., Liu C. Y., et al. (2007). Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation 116 (1), 39–48. 10.1161/CIRCULATIONAHA.106.675355 PubMed DOI

Gabbin B., Meraviglia V., Mummery C. L., Rabelink T. J., van Meer B. J., van den Berg C. W., et al. (2022). Toward human models of cardiorenal syndrome PubMed DOI PMC

Gevaert A. B., Shakeri H., Leloup A. J., Van Hove C. E., De Meyer G. R. Y., Vrints C. J., et al. (2017). Endothelial senescence contributes to heart failure with preserved ejection fraction in an aging mouse model. Circ. Heart Fail 10 (6), e003806. 10.1161/CIRCHEARTFAILURE.116.003806 PubMed DOI

Gomes P., Simao S., Silva E., Pinto V., Amaral J. S., Afonso J., et al. (2009). Aging increases oxidative stress and renal expression of oxidant and antioxidant enzymes that are associated with an increased trend in systolic blood pressure. Oxid. Med. Cell Longev. 2 (3), 138–145. 10.4161/oxim.2.3.8819 PubMed DOI PMC

Guo W., Pirtskhalava T., Tchkonia T., Xie W., Thomou T., Han J., et al. (2007). Aging results in paradoxical susceptibility of fat cell progenitors to lipotoxicity. Am. J. Physiol. Endocrinol. Metab. 292 (4), E1041–E1051. 10.1152/ajpendo.00557.2006 PubMed DOI

Harrison D. E., Strong R., Sharp Z. D., Nelson J. F., Astle C. M., Flurkey K., et al. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460 (7253), 392–395. 10.1038/nature08221 PubMed DOI PMC

Hayflick L. (1965). The limited PubMed DOI

Hemann M. T., Strong M. A., Hao L. Y., Greider C. W. (2001). The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107 (1), 67–77. 10.1016/s0092-8674(01)00504-9 PubMed DOI

Hohensinner P. J., Kaun C., Ebenbauer B., Hackl M., Demyanets S., Richter D., et al. (2018). Reduction of premature aging markers after gastric bypass surgery in morbidly obese patients. Obes. Surg. 28 (9), 2804–2810. 10.1007/s11695-018-3247-3 PubMed DOI PMC

Hubackova S., Davidova E., Rohlenova K., Stursa J., Werner L., Andera L., et al. (2019). Selective elimination of senescent cells by mitochondrial targeting is regulated by ANT2. Cell Death Differ. 26 (2), 276–290. 10.1038/s41418-018-0118-3 PubMed DOI PMC

Ibrahim M. M. (2010). Subcutaneous and visceral adipose tissue: structural and functional differences. Obes. Rev. 11 (1), 11–18. 10.1111/j.1467-789X.2009.00623.x PubMed DOI

Ihm S. H., Moon H. J., Kang J. G., Park C. Y., Oh K. W., Jeong I. K., et al. (2007). Effect of aging on insulin secretory function and expression of beta cell function-related genes of islets. Diabetes Res. Clin. Pract. 77 (Suppl. 1), S150–S154. 10.1016/j.diabres.2007.01.049 PubMed DOI

Joussen A. M., Poulaki V., Le M. L., Koizumi K., Esser C., Janicki H., et al. (2004). A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB J. 18 (12), 1450–1452. 10.1096/fj.03-1476fje PubMed DOI

Kahn S. E., Hull R. L., Utzschneider K. M. (2006). Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444 (7121), 840–846. 10.1038/nature05482 PubMed DOI

Kang T. W., Yevsa T., Woller N., Hoenicke L., Wuestefeld T., Dauch D., et al. (2011). Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479 (7374), 547–551. 10.1038/nature10599 PubMed DOI

Kim H. W., Shi H., Winkler M. A., Lee R., Weintraub N. L. (2020). Perivascular adipose tissue and vascular perturbation/atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 40 (11), 2569–2576. 10.1161/ATVBAHA.120.312470 PubMed DOI PMC

Kim M. N., Moon J. H., Cho Y. M. (2021). Sodium-glucose cotransporter-2 inhibition reduces cellular senescence in the diabetic kidney by promoting ketone body-induced NRF2 activation. Diabetes Obes. Metab. 23 (11), 2561–2571. 10.1111/dom.14503 PubMed DOI

Kimura R., Okouchi M., Fujioka H., Ichiyanagi A., Ryuge F., Mizuno T., et al. (2009). Glucagon-like peptide-1 (GLP-1) protects against methylglyoxal-induced PC12 cell apoptosis through the PI3K/Akt/mTOR/GCLc/redox signaling pathway. Neuroscience 162 (4), 1212–1219. 10.1016/j.neuroscience.2009.05.025 PubMed DOI

Kirkland J. L., Dobson D. E. (1997). Preadipocyte function and aging: links between age-related changes in cell dynamics and altered fat tissue function. J. Am. Geriatr. Soc. 45 (8), 959–967. 10.1111/j.1532-5415.1997.tb02967.x PubMed DOI

Kiss K., Regos E., Rada K., Firneisz G., Baghy K., Kovalszky I. (2020). Chronic hyperglycaemia induced alterations of hepatic stellate cells differ from the effect of TGFB1, and point toward metabolic stress. Pathol. Oncol. Res. 26 (1), 291–299. 10.1007/s12253-018-0458-9 PubMed DOI

Kruglikov I. L., Scherer P. E. (2020). The role of adipocytes and adipocyte-like cells in the severity of COVID-19 infections. Obes. (Silver Spring) 28 (7), 1187–1190. 10.1002/oby.22856 PubMed DOI PMC

Krupczak-Hollis K., Wang X., Dennewitz M. B., Costa R. H. (2003). Growth hormone stimulates proliferation of old-aged regenerating liver through forkhead box m1b. Hepatology 38 (6), 1552–1562. 10.1016/j.hep.2003.08.052 PubMed DOI

Kuki S., Imanishi T., Kobayashi K., Matsuo Y., Obana M., Akasaka T. (2006). Hyperglycemia accelerated endothelial progenitor cell senescence via the activation of p38 mitogen-activated protein kinase. Circ. J. 70 (8), 1076–1081. 10.1253/circj.70.1076 PubMed DOI

Kulkarni A. S., Brutsaert E. F., Anghel V., Zhang K., Bloomgarden N., Pollak M., et al. (2018). Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults. Aging Cell 17 (2), e12723. 10.1111/acel.12723 PubMed DOI PMC

Kurz D. J., Decary S., Hong Y., Erusalimsky J. D. (2000). Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J. Cell Sci. 113 (Pt 20), 3613–3622. 10.1242/jcs.113.20.3613 PubMed DOI

Le P., Tatar M., Dasarathy S., Alkhouri N., Herman W. H., Taksler G. B., et al. (2025). Estimated burden of metabolic dysfunction-associated steatotic liver disease in US adults, 2020 to 2050. JAMA Netw. Open 8 (1), e2454707. 10.1001/jamanetworkopen.2024.54707 PubMed DOI PMC

Leasher J. L., Bourne R. R., Flaxman S. R., Jonas J. B., Keeffe J., Naidoo K., et al. (2016). Global estimates on the number of people blind or visually impaired by diabetic retinopathy: a meta-analysis from 1990 to 2010. Diabetes Care 39 (9), 1643–1649. 10.2337/dc15-2171 PubMed DOI

Lefevre C., Chartoire D., Ferraz J. C., Verdier T., Pinteur C., Chanon S., et al. (2021). Obesity activates immunomodulating properties of mesenchymal stem cells in adipose tissue with differences between localizations. FASEB J. 35 (6), e21650. 10.1096/fj.202002046RR PubMed DOI

Lewis-McDougall F. C., Ruchaya P. J., Domenjo-Vila E., Teoh T. S., Prata L., Cottle B. J., et al. (2019). Aged-senescent cells contribute to impaired heart regeneration. Aging Cell 18 (3), e12931. 10.1111/acel.12931 PubMed DOI PMC

Liao Y. L., Fang Y. F., Sun J. X., Dou G. R. (2024). Senescent endothelial cells: a potential target for diabetic retinopathy. Angiogenesis 27 (4), 663–679. 10.1007/s10456-024-09943-7 PubMed DOI PMC

Liu J., Yang J. R., Chen X. M., Cai G. Y., Lin L. R., He Y. N. (2015). Impact of ER stress-regulated ATF4/p16 signaling on the premature senescence of renal tubular epithelial cells in diabetic nephropathy. Am. J. Physiol. Cell Physiol. 308 (8), C621–C630. 10.1152/ajpcell.00096.2014 PubMed DOI

Madonna R., Doria V., Minnucci I., Pucci A., Pierdomenico D. S., De Caterina R. (2020). Empagliflozin reduces the senescence of cardiac stromal cells and improves cardiac function in a murine model of diabetes. J. Cell Mol. Med. 24 (21), 12331–12340. 10.1111/jcmm.15699 PubMed DOI PMC

Maechler P., Carobbio S., Rubi B. (2006). In beta-cells, mitochondria integrate and generate metabolic signals controlling insulin secretion. Int. J. Biochem. Cell Biol. 38 (5-6), 696–709. 10.1016/j.biocel.2005.12.006 PubMed DOI

Maejima Y. (2019). SGLT2 inhibitors play a salutary role in heart failure via modulation of the mitochondrial function. Front. Cardiovasc Med. 6, 186. 10.3389/fcvm.2019.00186 PubMed DOI PMC

Martin-Montalvo A., Mercken E. M., Mitchell S. J., Palacios H. H., Mote P. L., Scheibye-Knudsen M., et al. (2013). Metformin improves healthspan and lifespan in mice. Nat. Commun. 4, 2192. 10.1038/ncomms3192 PubMed DOI PMC

Matloch Z., Cinkajzlova A., Mraz M., Haluzik M. (2018). The role of inflammation in epicardial adipose tissue in heart diseases. Curr. Pharm. Des. 24 (3), 297–309. 10.2174/1381612824666180110102125 PubMed DOI

Mehmel M., Jovanovic N., Spitz U. (2020). Nicotinamide riboside-the current state of research and therapeutic uses. Nutrients 12 (6), 1616. 10.3390/nu12061616 PubMed DOI PMC

Meng A., Wang Y., Van Zant G., Zhou D. (2003). Ionizing radiation and busulfan induce premature senescence in murine bone marrow hematopoietic cells. Cancer Res. 63 (17), 5414–5419. PubMed

Miao X. Y., Gu Z. Y., Liu P., Hu Y., Li L., Gong Y. P., et al. (2013). The human glucagon-like peptide-1 analogue liraglutide regulates pancreatic beta-cell proliferation and apoptosis via an AMPK/mTOR/P70S6K signaling pathway. Peptides 39, 71–79. 10.1016/j.peptides.2012.10.006 PubMed DOI

Mills K. F., Yoshida S., Stein L. R., Grozio A., Kubota S., Sasaki Y., et al. (2016). Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 24 (6), 795–806. 10.1016/j.cmet.2016.09.013 PubMed DOI PMC

Mittal N., Siddiqi H., Madamba E., Richards L., Bettencourt R., Ajmera V., et al. (2024). A prospective study on the prevalence of at-risk MASH in patients with type 2 diabetes mellitus in the United States. Aliment. Pharmacol. Ther. 59 (12), 1571–1578. 10.1111/apt.17997 PubMed DOI

Miyamoto K., Khosrof S., Bursell S. E., Rohan R., Murata T., Clermont A. C., et al. (1999). Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc. Natl. Acad. Sci. U. S. A. 96 (19), 10836–10841. 10.1073/pnas.96.19.10836 PubMed DOI PMC

Mosteiro L., Pantoja C., Alcazar N., Marion R. M., Chondronasiou D., Rovira M., et al. (2016). Tissue damage and senescence provide critical signals for cellular reprogramming PubMed DOI

Munoz-Espin D., Canamero M., Maraver A., Gomez-Lopez G., Contreras J., Murillo-Cuesta S., et al. (2013). Programmed cell senescence during mammalian embryonic development. Cell 155 (5), 1104–1118. 10.1016/j.cell.2013.10.019 PubMed DOI

Nambiar A., Kellogg D., 3rd, Justice J., Goros M., Gelfond J., Pascual R., et al. (2023). Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability. EBioMedicine 90, 104481. 10.1016/j.ebiom.2023.104481 PubMed DOI PMC

Nawaz S. S., Siddiqui K. (2022). Plasminogen activator inhibitor-1 mediate downregulation of adiponectin in type 2 diabetes patients with metabolic syndrome. Cytokine x. 4 (1), 100064. 10.1016/j.cytox.2022.100064 PubMed DOI PMC

Nehme J., Yang D., Altulea A., Varela-Eirin M., Wang L., Hu S., et al. (2023). High dietary protein and fat contents exacerbate hepatic senescence and SASP in mice. FEBS J. 290 (5), 1340–1347. 10.1111/febs.16292 PubMed DOI

Ning Y. C., Cai G. Y., Zhuo L., Gao J. J., Dong D., Cui S., et al. (2013). Short-term calorie restriction protects against renal senescence of aged rats by increasing autophagic activity and reducing oxidative damage. Mech. Ageing Dev. 134 (11-12), 570–579. 10.1016/j.mad.2013.11.006 PubMed DOI

Nordheim E., Geir Jenssen T. (2021). Chronic kidney disease in patients with diabetes mellitus. Endocr. Connect. 10 (5), R151–R159. 10.1530/EC-21-0097 PubMed DOI PMC

Obesity (2000). Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech. Rep. Ser. 894, 1–253. Available online at: https://pubmed.ncbi.nlm.nih.gov/11234459/ PubMed

Ogrodnik M., Miwa S., Tchkonia T., Tiniakos D., Wilson C. L., Lahat A., et al. (2017). Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691. 10.1038/ncomms15691 PubMed DOI PMC

Ogrodnik M., Zhu Y., Langhi L. G. P., Tchkonia T., Kruger P., Fielder E., et al. (2019). Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Cell Metab. 29 (5), 1061–1077. 10.1016/j.cmet.2018.12.008 PubMed DOI PMC

Ogurtsova K., da Rocha Fernandes J. D., Huang Y., Linnenkamp U., Guariguata L., Cho N. H., et al. (2017). IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res. Clin. Pract. 128, 40–50. 10.1016/j.diabres.2017.03.024 PubMed DOI

Okabe K., Yaku K., Uchida Y., Fukamizu Y., Sato T., Sakurai T., et al. (2022). Oral administration of nicotinamide mononucleotide is safe and efficiently increases blood nicotinamide adenine dinucleotide levels in healthy subjects. Front. Nutr. 9, 868640. 10.3389/fnut.2022.868640 PubMed DOI PMC

Ortiz L. A., Lasky J., Hamilton R. F., Jr., Holian A., Hoyle G. W., Banks W., et al. (1998). Expression of TNF and the necessity of TNF receptors in bleomycin-induced lung injury in mice. Exp. Lung Res. 24 (6), 721–743. 10.3109/01902149809099592 PubMed DOI

Ortiz L. A., Lasky J., Lungarella G., Cavarra E., Martorana P., Banks W. A., et al. (1999). Upregulation of the p75 but not the p55 TNF-alpha receptor mRNA after silica and bleomycin exposure and protection from lung injury in double receptor knockout mice. Am. J. Respir. Cell Mol. Biol. 20 (4), 825–833. 10.1165/ajrcmb.20.4.3193 PubMed DOI

Oubaha M., Miloudi K., Dejda A., Guber V., Mawambo G., Germain M. A., et al. (2016). Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy. Sci. Transl. Med. 8 (362), 362ra144. 10.1126/scitranslmed.aaf9440 PubMed DOI

Owen M. R., Doran E., Halestrap A. P. (2000). Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 348 (Pt 3), 607–614. 10.1042/bj3480607 PubMed DOI PMC

Palmer A. K., Tchkonia T., LeBrasseur N. K., Chini E. N., Xu M., Kirkland J. L. (2015). Cellular senescence in type 2 diabetes: a therapeutic opportunity. Diabetes 64 (7), 2289–2298. 10.2337/db14-1820 PubMed DOI PMC

Palmer A. K., Xu M., Zhu Y., Pirtskhalava T., Weivoda M. M., Hachfeld C. M., et al. (2019). Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell 18 (3), e12950. 10.1111/acel.12950 PubMed DOI PMC

Pan X. X., Yao K. L., Yang Y. F., Ge Q., Zhang R., Gao P. J., et al. (2021). Senescent T cell induces Brown adipose tissue “whitening” PubMed DOI PMC

Park S. J., Ahmad F., Philp A., Baar K., Williams T., Luo H., et al. (2012). Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148 (3), 421–433. 10.1016/j.cell.2012.01.017 PubMed DOI PMC

Patro B. S., Frohlich R., Bohr V. A., Stevnsner T. (2011). WRN helicase regulates the ATR-CHK1-induced S-phase checkpoint pathway in response to topoisomerase-I-DNA covalent complexes. J. Cell Sci. 124 (Pt 23), 3967–3979. 10.1242/jcs.081372 PubMed DOI PMC

Peng W., Zhou R., Sun Z. F., Long J. W., Gong Y. Q. (2022). Novel insights into the roles and mechanisms of GLP-1 receptor agonists against aging-related diseases. Aging Dis. 13 (2), 468–490. 10.14336/AD.2021.0928 PubMed DOI PMC

Perry R. J., Samuel V. T., Petersen K. F., Shulman G. I. (2014). The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 510 (7503), 84–91. 10.1038/nature13478 PubMed DOI PMC

Polonis K., Becari C., Chahal C. A. A., Zhang Y., Allen A. M., Kellogg T. A., et al. (2020). Chronic intermittent hypoxia triggers a senescence-like phenotype in human white preadipocytes. Sci. Rep. 10 (1), 6846. 10.1038/s41598-020-63761-7 PubMed DOI PMC

Pradhan A. D., Manson J. E., Rifai N., Buring J. E., Ridker P. M. (2001). C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286 (3), 327–334. 10.1001/jama.286.3.327 PubMed DOI

Raicevic B., Jankovic S. (2023). Predictors of gastrointestinal complaints in patients on metformin therapy. Open Med. (Wars). 18 (1), 20230871. 10.1515/med-2023-0871 PubMed DOI PMC

Reers C., Erbel S., Esposito I., Schmied B., Buchler M. W., Nawroth P. P., et al. (2009). Impaired islet turnover in human donor pancreata with aging. Eur. J. Endocrinol. 160 (2), 185–191. 10.1530/EJE-08-0596 PubMed DOI

Rex N., Melk A., Schmitt R. (2023). Cellular senescence and kidney aging. Clin. Sci. (Lond). 137 (24), 1805–1821. 10.1042/CS20230140 PubMed DOI PMC

Rohlenova K., Sachaphibulkij K., Stursa J., Bezawork-Geleta A., Blecha J., Endaya B., et al. (2017). Selective disruption of respiratory supercomplexes as a new strategy to suppress her2(high) breast cancer. Antioxid. Redox Signal 26 (2), 84–103. 10.1089/ars.2016.6677 PubMed DOI PMC

Sabin R. J., Anderson R. M. (2011). Cellular Senescence - its role in cancer and the response to ionizing radiation. Genome Integr. 2 (1), 7. 10.1186/2041-9414-2-7 PubMed DOI PMC

Salam R., Saliou A., Bielle F., Bertrand M., Antoniewski C., Carpentier C., et al. (2023). Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma. Nat. Commun. 14 (1), 441. 10.1038/s41467-023-36124-9 PubMed DOI PMC

Sasaki N., Itakura Y., Toyoda M. (2020). Rapamycin promotes endothelial–mesenchymal transition during stress-induced premature senescence through the activation of autophagy. Cell Commun. Signal. 18 (1), 43. 10.1186/s12964-020-00533-w PubMed DOI PMC

Schafer M. J., White T. A., Iijima K., Haak A. J., Ligresti G., Atkinson E. J., et al. (2017). Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun. 8, 14532. 10.1038/ncomms14532 PubMed DOI PMC

Serrano M., Lin A. W., McCurrach M. E., Beach D., Lowe S. W. (1997). Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88 (5), 593–602. 10.1016/s0092-8674(00)81902-9 PubMed DOI

Sgalla G., Iovene B., Calvello M., Ori M., Varone F., Richeldi L. (2018). Idiopathic pulmonary fibrosis: pathogenesis and management. Respir. Res. 19 (1), 32. 10.1186/s12931-018-0730-2 PubMed DOI PMC

Shimokawa I., Higami Y., Tsuchiya T., Otani H., Komatsu T., Chiba T., et al. (2003). Life span extension by reduction of the growth hormone-insulin-like growth factor-1 axis: relation to caloric restriction. FASEB J. 17 (9), 1108–1109. 10.1096/fj.02-0819fje PubMed DOI

Shioya S., Masuda T., Senoo T., Horimasu Y., Miyamoto S., Nakashima T., et al. (2018). Plasminogen activator inhibitor-1 serves an important role in radiation-induced pulmonary fibrosis. Exp. Ther. Med. 16 (4), 3070–3076. 10.3892/etm.2018.6550 PubMed DOI PMC

Shivshankar P., Brampton C., Miyasato S., Kasper M., Thannickal V. J., Le Saux C. J. (2012). Caveolin-1 deficiency protects from pulmonary fibrosis by modulating epithelial cell senescence in mice. Am. J. Respir. Cell Mol. Biol. 47 (1), 28–36. 10.1165/rcmb.2011-0349OC PubMed DOI PMC

Sis B., Tasanarong A., Khoshjou F., Dadras F., Solez K., Halloran P. F. (2007). Accelerated expression of senescence associated cell cycle inhibitor p16INK4A in kidneys with glomerular disease. Kidney Int. 71 (3), 218–226. 10.1038/sj.ki.5002039 PubMed DOI

Sofue T., Kushida Y., Ozaki T., Moritoki M., Nishijima Y., Ohsaki H., et al. (2018). Tubular cell senescence in the donated kidney predicts allograft function, but not donor remnant kidney function, in living donor kidney transplantation. Am. J. Nephrol. 47 (1), 8–17. 10.1159/000485845 PubMed DOI

Sone H., Kagawa Y. (2005). Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice. Diabetologia 48 (1), 58–67. 10.1007/s00125-004-1605-2 PubMed DOI

Song K. H., Jeong J. S., Kim M. K., Kwon H. S., Baek K. H., Ko S. H., et al. (2019). Discordance in risk factors for the progression of diabetic retinopathy and diabetic nephropathy in patients with type 2 diabetes mellitus. J. Diabetes Investig. 10 (3), 745–752. 10.1111/jdi.12953 PubMed DOI PMC

Sookoian S., Pirola C. J. (2011). Metabolic syndrome: from the genetics to the pathophysiology. Curr. Hypertens. Rep. 13 (2), 149–157. 10.1007/s11906-010-0164-9 PubMed DOI

Soriani A., Zingoni A., Cerboni C., Iannitto M. L., Ricciardi M. R., Di Gialleonardo V., et al. (2009). ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood 113 (15), 3503–3511. 10.1182/blood-2008-08-173914 PubMed DOI

Supale S., Thorel F., Merkwirth C., Gjinovci A., Herrera P. L., Scorrano L., et al. (2013). Loss of prohibitin induces mitochondrial damages altering beta-cell function and survival and is responsible for gradual diabetes development. Diabetes 62 (10), 3488–3499. 10.2337/db13-0152 PubMed DOI PMC

Tchkonia T., Morbeck D. E., Von Zglinicki T., Van Deursen J., Lustgarten J., Scrable H., et al. (2010). Fat tissue, aging, and cellular senescence. Aging Cell 9 (5), 667–684. 10.1111/j.1474-9726.2010.00608.x PubMed DOI PMC

Tencerova M., Frost M., Figeac F., Nielsen T. K., Ali D., Lauterlein J. L., et al. (2019). Obesity-associated hypermetabolism and accelerated senescence of bone marrow stromal stem cells suggest a potential mechanism for bone fragility. Cell Rep. 27 (7), 2050–2062. 10.1016/j.celrep.2019.04.066 PubMed DOI

Trnovska J., Svoboda P., Pelantova H., Kuzma M., Kratochvilova H., Kasperova B. J., et al. (2021). Complex positive effects of SGLT-2 inhibitor empagliflozin in the liver, kidney and adipose tissue of hereditary hypertriglyceridemic rats: possible contribution of attenuation of cell senescence and oxidative stress. Int. J. Mol. Sci. 22 (19), 10606. 10.3390/ijms221910606 PubMed DOI PMC

Tsuji S., Minami S., Hashimoto R., Konishi Y., Suzuki T., Kondo T., et al. (2022). SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response. Nat. Aging 2 (2), 115–124. 10.1038/s43587-022-00170-7 PubMed DOI PMC

Vacurova E., Trnovska J., Svoboda P., Skop V., Novosadova V., Reguera D. P., et al. (2022). Mitochondrially targeted tamoxifen alleviates markers of obesity and type 2 diabetes mellitus in mice. Nat. Commun. 13 (1), 1866. 10.1038/s41467-022-29486-z PubMed DOI PMC

Vacurova E., Vlachova E., Stursa J., Bohacova K., Havrlantova T., Skop V., et al. (2025). Targeting mitochondrial integrity as a new senolytic strategy. Aging Dis. 10.14336/AD.2024.1100 PubMed DOI

van Deursen J. M. (2014). The role of senescent cells in ageing. Nature 509 (7501), 439–446. 10.1038/nature13193 PubMed DOI PMC

Verzola D., Gandolfo M. T., Gaetani G., Ferraris A., Mangerini R., Ferrario F., et al. (2008). Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy. Am. J. Physiol. Ren. Physiol. 295 (5), F1563–F1573. 10.1152/ajprenal.90302.2008 PubMed DOI

Villaret A., Galitzky J., Decaunes P., Esteve D., Marques M. A., Sengenes C., et al. (2010). Adipose tissue endothelial cells from obese human subjects: differences among depots in angiogenic, metabolic, and inflammatory gene expression and cellular senescence. Diabetes 59 (11), 2755–2763. 10.2337/db10-0398 PubMed DOI PMC

Wadden T. A., Chao A. M., Machineni S., Kushner R., Ard J., Srivastava G., et al. (2023). Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial. Nat. Med. 29 (11), 2909–2918. 10.1038/s41591-023-02597-w PubMed DOI PMC

Wang C., Maddick M., Miwa S., Jurk D., Czapiewski R., Saretzki G., et al. (2010). Adult-onset, short-term dietary restriction reduces cell senescence in mice. Aging (Albany NY) 2 (9), 555–566. 10.18632/aging.100196 PubMed DOI PMC

Wang Q., Wang J., Wang P., Wang L., Jia L., Ling X., et al. (2019). Glycemic control is associated with atrial structural remodeling in patients with type 2 diabetes. BMC Cardiovasc Disord. 19 (1), 278. 10.1186/s12872-019-1249-2 PubMed DOI PMC

Wang R., Yu Z., Sunchu B., Shoaf J., Dang I., Zhao S., et al. (2017). Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism. Aging Cell 16 (3), 564–574. 10.1111/acel.12587 PubMed DOI PMC

Wiley C. D., Campisi J. (2021). The metabolic roots of senescence: mechanisms and opportunities for intervention. Nat. Metab. 3 (10), 1290–1301. 10.1038/s42255-021-00483-8 PubMed DOI PMC

Wilkinson E., Waqar M., Sinclair A., Randhawa G. (2016). Meeting the challenge of diabetes in ageing and diverse populations: a review of the literature from the UK. J. Diabetes Res. 2016, 8030627. 10.1155/2016/8030627 PubMed DOI PMC

Wissler G. E. O., Misra A., Netto J. M. E., Tchkonia T., Kirkland J. L. (2021). Strategies for late phase preclinical and early clinical trials of senolytics. Mech. Ageing Dev. 200, 111591. 10.1016/j.mad.2021.111591 PubMed DOI PMC

Xia Y., Jin J., Sun Y., Kong X., Shen Z., Yan R., et al. (2024). Tirzepatide's role in targeting adipose tissue macrophages to reduce obesity-related inflammation and improve insulin resistance. Int. Immunopharmacol. 143 (Pt 2), 113499. 10.1016/j.intimp.2024.113499 PubMed DOI

Xu M., Palmer A. K., Ding H., Weivoda M. M., Pirtskhalava T., White T. A., et al. (2015). Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife 4, e12997. 10.7554/eLife.12997 PubMed DOI PMC

Xu M., Pirtskhalava T., Farr J. N., Weigand B. M., Palmer A. K., Weivoda M. M., et al. (2018). Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24 (8), 1246–1256. 10.1038/s41591-018-0092-9 PubMed DOI PMC

Yoshino J., Mills K. F., Yoon M. J., Imai S. (2011). Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 14 (4), 528–536. 10.1016/j.cmet.2011.08.014 PubMed DOI PMC

Younossi Z. M., Golabi P., Price J. K., Owrangi S., Gundu-Rao N., Satchi R., et al. (2024). The global epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among patients with type 2 diabetes. Clin. Gastroenterol. Hepatol. 22 (10), 1999–2010 e8. 10.1016/j.cgh.2024.03.006 PubMed DOI

Yousefzadeh M. J., Zhu Y., McGowan S. J., Angelini L., Fuhrmann-Stroissnigg H., Xu M., et al. (2018). Fisetin is a senotherapeutic that extends health and lifespan. eBioMedicine 36, 18–28. 10.1016/j.ebiom.2018.09.015 PubMed DOI PMC

Zhang D., Lu H., Chen Z., Wang Y., Lin J., Xu S., et al. (2017). High glucose induces the aging of mesenchymal stem cells via Akt/mTOR signaling. Mol. Med. Rep. 16 (2), 1685–1690. 10.3892/mmr.2017.6832 PubMed DOI PMC

Zheng Z., Bian Y., Zhang Y., Ren G., Li G. (2020). Metformin activates AMPK/SIRT1/NF-κB pathway and induces mitochondrial dysfunction to drive caspase3/GSDME-mediated cancer cell pyroptosis. Cell Cycle 19 (10), 1089–1104. 10.1080/15384101.2020.1743911 PubMed DOI PMC

Zhong W. L., Zou G. L., Gu J. Q., Zhang J. (2010). L-arginine attenuates high glucose-accelerated senescence in human umbilical vein endothelial cells. Diabetes Res. Clin. P. R. 89 (1), 38–45. 10.1016/j.diabres.2010.03.013 PubMed DOI

Zhou L., Chen X., Lu M., Wu Q., Yuan Q., Hu C., et al. (2019). Wnt/β-catenin links oxidative stress to podocyte injury and proteinuria. Kidney Int. 95 (4), 830–845. 10.1016/j.kint.2018.10.032 PubMed DOI PMC

Zhu F., Li Y., Zhang J., Piao C., Liu T., Li H. H., et al. (2013). Senescent cardiac fibroblast is critical for cardiac fibrosis after myocardial infarction. PLoS One 8 (9), e74535. 10.1371/journal.pone.0074535 PubMed DOI PMC

Zhu X., Zhang C., Liu L., Xu L., Yao L. (2024). Senolytic combination of dasatinib and quercetin protects against diabetic kidney disease by activating autophagy to alleviate podocyte dedifferentiation via the Notch pathway. Int. J. Mol. Med. 53 (3), 26. 10.3892/ijmm.2024.5350 PubMed DOI PMC

Zhu Y., Tchkonia T., Pirtskhalava T., Gower A. C., Ding H., Giorgadze N., et al. (2015). The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14 (4), 644–658. 10.1111/acel.12344 PubMed DOI PMC

Zizka O., Haluzik M., Jude E. B. (2024). Pharmacological treatment of obesity in older adults. Drugs Aging 41 (11), 881–896. 10.1007/s40266-024-01150-9 PubMed DOI PMC