PREMATURE CARDIOVASCULAR AGING IN PATIENTS WITH OBESITY: FROM CELLULAR SENESCENCE OF MACROPHAGES AND MEZENCHYMAL STROMAL CELLS TO CLINICAL MANIFESTATION (REVIEW OF REVIEWS)

Highlights

• Obesity induces premature senescence of mesenchymal stromal cells through p38MAPK/NF-κB pathway activation with SASP phenotype formation.
• SASP factors (IL-6, TNF-α, MCP-1) promote macrophage polarization to proinflammatory M1 phenotype, creating a vicious cycle of chronic inflammation.
• Accumulation of senescent cells is associated with biological age acceleration by 3–4 years and increased cardiovascular disease risk.
• Senolytic and senomorphic therapy demonstrate promise in experimental models and require clinical validation.

Abstract

Obesity is a significant risk factor for the premature development of cardiovascular diseases and the acceleration of biological aging. The accumulation of senescent cells in adipose tissue, including mesenchymal stromal cells (MSCs) and macrophages, plays a key role in this process. These cells provoke chronic inflammation (inflamaging) and contribute to the development of cardiovascular pathology. As part of the study, an umbrella review was conducted based on the Joanna Briggs Institute methodology and the PRISMA 2020 guidelines. The analysis included 45 systematic reviews and meta–analyses from the PubMed/MEDLINE, Web of Science, Scopus, and Cochrane Library databases (search period 2019–2026). The methodological quality of the work was assessed using the AMSTAR tool‑2. The results showed that obesity triggers premature MSCs senescence through activation of the p38MAPK/NF-kB signaling pathways. This leads to: increased expression of aging markers (p16INK4a, p21Cip1, p53); formation of a secretory phenotype associated with senescence (SASP). SASP factors (IL‑6, TNF‑α, MCP‑1) cause the polarization of macrophages into the proinflammatory M1 phenotype. As a result, tissue inflammation and endothelial dysfunction worsen. In addition, it was found that the accumulation of senescent cells accelerates the epigenetic age by 3–4 years in obese patients (indicators ΔPhenoAge and DNAmGrimAge). Clinically, this is manifested by an increased risk of: atherosclerosis; heart failure with preserved ejection fraction; atrial fibrillation. Thus, the cellular senescence of MSCs and macrophages is an important pathogenetic link in premature cardiovascular aging in obesity. Senolytics (drugs for the elimination of senescent cells) and cenomorphics (agents for the suppression of SASP) may become promising areas of therapy. However, their effectiveness requires further clinical testing.

1. World Health Organization. Obesity and overweight. Fact sheet. 2024. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight.

2. Ruperez C, Madeo F, de Cabo R, et al. Obesity accelerates cardiovascular ageing. Eur Heart J. 2024;46(23):2161-2185. doi: 10.1093/eurheartj/ehaf216.

3. Tam BT, Morais JA, Santosa S. Obesity and ageing: two sides of the same coin. Obes Rev. 2020;21(4):e12991. doi: 10.1111/obr.12991.

4. López-Otín C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell. 2013;153(6):1194-1217. doi: 10.1016/j.cell.2013.05.039.

5. Horvath S, Erhart W, Brosch M, et al. Obesity accelerates epigenetic aging of human liver. Proc Natl Acad Sci USA. 2014;111(43):15538-15543. doi: 10.1073/pnas.1412759111.

6. Hu L, Li J, Tang Z, et al. How does biological age acceleration mediate the associations of obesity with cardiovascular disease? Evidence from international multi-cohort studies. BMC Med. 2024;23:189. doi: 10.1186/s12933-025-02770-0.

7. Xu C, Qiu Z, Guo Q, et al. The role of cellular senescence in cardiovascular disease. Cell Death Discov. 2025;11:431. doi: 10.1038/s41420-025-02720-5.

8. Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99-118. doi: 10.1146/annurev-pathol-121808-102144.

9. Wang B, Han J, Elisseeff J, Demaris M. The senescence-associated secretory phenotype and its physiological and pathological implications. Nat Rev Mol Cell Biol. 2024;25(12):834-856. doi: 10.1038/s41580-024-00727-x.

10. Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol. 2018;15(9):505-522. doi: 10.1038/s41569-018-0064-2.

11. Franceschi C, Garagnani P, Parini P, et al. Inflammageing: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576-590. doi: 10.1038/s41574-018-0059-4.

12. Conley SM, Hickson LJ, Kellog TA, et al. Human obesity induces dysfunction and early senescence in adipose tissue-derived mesenchymal stromal/stem cells. Front Cell Dev Biol. 2020;8:197. doi: 10.3389/fcell.2020.00197.

13. Lee BC, Yu KR. Impact of mesenchymal stem cell senescence on inflammageing. BMB Rep. 2020;53(2):65-73. doi: 10.5483/BMBRep.2020.53.2.291.

14. Alessio N, Acar MB, Demirsoy IH, et al. Obesity is associated with senescence of mesenchymal stromal cells derived from bone marrow, subcutaneous and visceral fat of young mice. Aging (Albany NY). 2020;12(12):12609-12621. doi: 10.18632/aging.103606.

15. Conley SM, Hickson LJ, Kellog TA, et al. Human obesity induces dysfunction and early senescence in adipose tissue-derived mesenchymal stromal/stem cells. Front Cell Dev Biol. 2020;8:197. doi: 10.3389/fcell.2020.00197.

16. Acosta JC, Banito A, Wuestefeld T, et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol. 2013;15(8):978-990. doi: 10.1038/ncb2784.

17. Wang YB, Li T, Wang FY, et al. The Dual Role of Cellular Senescence in Macrophages. Int J Biol Sci. 2025;21:632-649. doi: 10.7150/ijbs.104404.

18. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117(1):175-184. doi: 10.1172/JCI29881.

19. Weisberg SP, McCann D, Desai M, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796-1808. doi: 10.1172/JCI19246.

20. Chen Y, Yang L, Li X. Advances in Mesenchymal stem cells regulating macrophage polarization and treatment of sepsis-induced liver injury. Front Immunol. 2023;14:1238972. doi: 10.3389/fimmu.2023.1238972.

21. Donato AJ, Machin DR, Lesniewski LA. Mechanisms of dysfunction in the aging vasculature and role in age-related disease. Circ Res. 2018;123(7):825-848. doi: 10.1161/circresaha.118.312563.

22. Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci. 2014;71(4):549-574. doi: 10.1007/s00018-013-1349-6.

23. Lavie CJ, Pandey A, Lau DH, et al. Obesity and atrial fibrillation prevalence, pathogenesis, and prognosis: effects of weight loss and exercise. J Am Coll Cardiol. 2017;70(16):2022-2035. doi: 10.1016/j.jacc.2017.09.002.

24. Ren J, Wu NN, Wang S, et al. Obesity cardiomyopathy: evidence, mechanisms, and therapeutic implications. Physiol Rev. 2021;101(4):1745-1807. doi: 10.1152/physrev.00030.2020.

25. Aromataris E, Fernandez R, Godfrey CM, et al. Summarizing systematic reviews: methodological development, conduct and reporting of an umbrella review approach. Int J Evid Based Healthc. 2015;13(3):132-140. doi: 10.1097/XEB.0000000000000055.

26. Abdellatif M, Dadam MN, Vu NT, et al. A step-by-step guide for conducting an umbrella review. BMC Med Res Methodol. 2025;25(1):215. doi: 10.1186/s41182-025-00764-y.

27. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi: 10.1136/bmj.n71.

28. Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008. doi: 10.1136/bmj.j4008.

29. Foti, R.; Storti, G.; Palmesano, M.; Scioli, M.G.; Fiorelli, E.; Terriaca, S.; Cervelli, G.; Kim, B.S.; Orlandi, A.; Cervelli, V. Senescence in Adipose-Derived Stem Cells: Biological Mechanisms and Therapeutic Challenges. Int. J. Mol. Sci. 2024; 25; 8390. doi: 10.3390/ijms25158390

30. Alessio N, Acar MB, Demirsoy IH, et al. Obesity is associated with senescence of mesenchymal stromal cells derived from bone marrow, subcutaneous and visceral fat of young mice. Aging (Albany NY). 2020;12(12):12609-12621. doi: 10.18632/aging.103606.

31. Widjaja SS, Rusdiana R, Helvi TM, Simanullang RH, Jayalie VF, Amelia R, Arisa J. Finding a Link between Obesity and Senescence: A Systematic Review and Meta-Analysis. Iran J Public Health. 2024;53(1):12-22. doi: 10.18502/ijph.v53i1.14679

32. Zhou S, Greenberger JS, Epperly MW, et al. Age-related intrinsic changes in human bone-marrow-derived mesenchymal stem cells and their differentiation to osteoblasts. Aging Cell. 2008;7(3):335-343. doi: 10.1111/j.1474-9726.2008.00377.x.

33. Blackburn EH, Epel ES, Lin J. Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection. Science. 2015;350(6265):1193-1198. doi: 10.1126/science.aab3389.

34. Yu JM, Wu X, Gimble JM, et al. Age-related changes in mesenchymal stem cells derived from rhesus macaque bone marrow. Aging Cell. 2011;10(1):66-79. doi: 10.1111/j.1474-9726.2010.00646.x.

35. Lee BC, Yu KR. Impact of mesenchymal stem cell senescence on inflammageing. BMB Rep. 2020;53(2):65-73. doi: 10.5483/BMBRep.2020.53.2.291.

36. Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99-118. doi: 10.1146/annurev-pathol-121808-102144.

37. Wan YCE, Dufau J, Spalding KL. Local and systemic impact of adipocyte senescence associated secretory profile. Current Opinion in Endocrine and Metabolic Research. 2024;37:100547. doi: 10.1016/j.coemr.2024.100547.

38. Acosta JC, Banito A, Wuestefeld T, et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol. 2013;15(8):978-990. doi: 10.1038/ncb2784.

39. Wang B, Han J, Elisseeff J, Demaris M. The senescence-associated secretory phenotype and its physiological and pathological implications. Nat Rev Mol Cell Biol. 2024;25(12):834-856. doi: 10.1038/s41580-024-00727-x.

40. Oduro PK, Zheng X, Wei X, et al. The cGAS-STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy. Acta Pharm Sin B. 2022;12(1):50-75. doi: 10.1016/j.apsb.2021.05.011.

41. Laberge RM, Sun Y, Orjalo AV, et al. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol. 2015;17(8):1049-1061. doi: 10.1038/ncb3195.

42. Alenezi SA, Khan R, Snell L, Aboeldalyl S, Amer S. The Role of NLRP3 Inflammasome in Obesity and PCOS-A Systematic Review and Meta-Analysis. Int J Mol Sci. 2023;24(13):10976. doi: 10.3390/ijms241310976.

43. Weisberg SP, McCann D, Desai M, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796-1808. doi: 10.1172/JCI19246.

44. Murano I, Barbatelli G, Parisani V, et al. Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. J Lipid Res. 2008;49(7):1562-1568. doi: 10.1194/jlr.M800019-JLR200.

45. Vera KFH, Hemakumar C, Bilachi RS, et al. Macrophage phenotypic switch and obesity-associated metabolic risk: mechanisms and targets. Oxid Med Cell Longev. 2025;2025:6710641. doi: 10.1155/omcl/6710641.

46. Li X, Ren Y, Chang K, et al. Adipose tissue macrophages as potential targets for obesity and metabolic diseases. Front Immunol. 2023;14:1153915. doi: 10.3389/fimmu.2023.1153915.

47. O'Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016;16(9):553-565. doi: 10.1038/nri.2016.70.

48. Ying W, Riopel M, Bandyopadhyay G, et al. Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Cell. 2017;171(2):372-384. doi: 10.1016/j.cell.2017.08.035.

49. Kumar M, Yan P, Kuchel GA, Xu M. Cellular senescence as a targetable risk factor for cardiovascular diseases: therapeutic implications. JACC Basic Transl Sci. 2024;9(4):522-534. doi: 10.1016/j.jacbts.2023.12.003.

50. Kanda H, Tateya S, Tamori Y, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest. 2006;116(6):1494-1505. doi: 10.1172/JCI26498.

51. Zhang, M., Wang, J., et al. (2024). "Emerging Landscape of Mesenchymal Stem Cell Senescence Mechanisms and Implications on Therapeutic Strategies". ACS Pharmacology & Translational Science. 2024; 7(8); 2315–2336. Doi: 10.1021/acsptsci.4c00284

52. Arias C, Alvarez-Indo J, Cifuentes M, et al. Enhancing adipose tissue functionality in obesity: senotherapeutics, autophagy and cellular senescence as a target. J Transl Med. 2024;22:709. doi: 10.1186/s40659-024-00531-z.

53. Arias C, Alvarez-Indo J, Cifuentes M, et al. Enhancing adipose tissue functionality in obesity: senotherapeutics, autophagy and cellular senescence as a target. J Transl Med. 2024;22:709. doi: 10.1186/s40659-024-00531-z.

54. Hickson LJ, Langhi Prata LGP, Bobart SA, et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019;47:446-456. doi: 10.1016/j.ebiom.2019.08.069.

55. Safaei S, Sohrabi S, Zahmatkesh P, et al. Exosomes in aging and age-related disorders: mechanisms, therapeutic potentials, and challenges. J Transl Med. 2025;23(1):423. doi: 10.1186/s12967-025-07379-1.

56. Calila H, Balasescu E, Nedelcu RI, Ion DA. Endothelial dysfunction as a key link between cardiovascular disease and frailty: a systematic review. J Clin Med. 2024;13(9):2686. doi: 10.3390/jcm13092686.

57. Widlansky ME, Gokce N, Keaney JF Jr, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol. 2003;42(7):1149-1160. doi: 10.1016/s0735-1097(03)00994-x.

58. Acosta JC, Banito A, Wuestefeld T, et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol. 2013;15(8):978-990. doi: 10.1038/ncb2784.

59. Conley SM, Hickson LJ, Kellog TA, et al. Human obesity induces dysfunction and early senescence in adipose tissue-derived mesenchymal stromal/stem cells. Front Cell Dev Biol. 2020;8:197. doi: 10.3389/fcell.2020.00197.

60. Donato, A. J., Morgan, R. G., Walker, A. E., & Lesniewski, L. A. "Vascular Aging: From Mechanisms to Interventions". GeroScience7 2022; 44(3), 1215–1242. DOI: 10.1007/s11357-022-00566-5

61. Travers JG, Kamal FA, Robbins J, et al. Cardiac fibrosis: the fibroblast awakens. Circ Res. 2016;118(6):1021-1040. doi: 10.1161/CIRCRESAHA.115.306565.

62. Pan W, Jie W, Huang H. Vascular calcification: molecular mechanisms and therapeutic interventions. MedComm.(2020). 2023;4(1):e200. doi: 10.1002/mco2.200.

63. Spinale FG. Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol Rev. 2007;87(4):1285-1342. doi: 10.1152/physrev.00012.2007.

64. Wang B, Jiang T, Qi Y, et al. AGE-RAGE Axis and Cardiovascular Diseases: Pathophysiologic Mechanisms and Prospects for Clinical Applications. Cardiovasc Drugs Ther. 2024. doi: 10.1007/s10557-024-07639-0.

65. Baker DJ, Childs BG, Durik M, et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature. 2016;530(7589):184-189. doi: 10.1038/nature16932.

66. Belsky DW, Caspi A, Arseneault L, et al. Quantification of the pace of biological aging in humans through a blood test, the DunedinPoAm DNA methylation algorithm. eLife. 2020;9:e54870. doi: 10.7554/eLife.54870.

67. Kumar M, Yan P, Kuchel GA, Xu M. Cellular senescence as a targetable risk factor for cardiovascular diseases: therapeutic implications. JACC Basic Transl Sci. 2024;9(4):522-534. doi: 10.1016/j.jacbts.2023.12.003.

68. Zyubanova I.V., Mordovin V.F., Lichikaki V.A., Manukyan M.A., Khunkhinova S.A., Solonskaya E.I., Rudenko V.V., Falkovskaya A.Yu. Vascular aging: the role of hypertension, obesity and meta-inflammation. "Arterial’naya Gipertenziya" ("Arterial Hypertension"). 2024;30(6):553–561. (In Russ.) https://doi.org/10.18705/1607-419X-2024-2474.

69. Arias C, Alvarez-Indo J, Cifuentes M, et al. Enhancing adipose tissue functionality in obesity: senotherapeutics, autophagy and cellular senescence as a target. J Transl Med. 2024;22:709. doi: 10.1186/s40659-024-00531-z.

70. Hickson LJ, Langhi Prata LGP, Bobart SA, et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019;47:446-456. doi: 10.1016/j.ebiom.2019.08.069.

71. Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020;288(5):518-536. doi: 10.1111/joim.13141.

72. Bitto A, Ito TK, Pineda VV, et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife. 2016;5:e16351. doi: 10.7554/eLife.16351.

73. Moiseeva O, Deschênes-Simard X, St-Germain E, et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell. 2013;12(3):489-498. doi: 10.1111/acel.12075.

74. Arabpour M, Saghazadeh A, Rezaei N. Anti-inflammatory and M2 macrophage polarization-promoting effect of mesenchymal stem cell-derived exosomes. Cytokine Growth Factor Rev. 2021;62:1-9. doi: 10.1016/j.intimp.2021.107823.

75. Kraus WE, Bhapkar M, Huffman KM, et al. 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. Lancet Diabetes Endocrinol. 2019;7(9):673-683. doi: 10.1016/S2213-8587(19)30151-2.

76. Batsis JA, Villareal DT. Sarcopenic obesity in older adults: aetiology, epidemiology and treatment strategies. Nat Rev Endocrinol. 2018;14(9):513-537. doi: 10.1038/s41574-018-0062-9.

77. Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 2021;9(10):653-662. doi: 10.1016/S2213-8587(21)00203-5.

78.