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Senesens. Heart. Senotherapy

https://doi.org/10.37489/2588-0519-2024-3-3-19

EDN: EZRHZW

Abstract

Senescence — cellular aging — is a special form of cell death, characterized by the cell’s irreversible loss of its proliferation potential and the development of resistance to apoptosis. Senescence is based on the attrition (shortening) of telomeres that occurs with each subsequent cell division, which ultimately leads to sustained DNA damage and subsequent activation of the cellular aging program. Senescent cells have a unique so-called senescence-associated secretory phenotype (SASP), i.e. the ability of aging cells to secrete into the extracellular environment a large number of pathogenic factors that act paracrine on undamaged cells and transfer them to a state of senescence. The literature review examines the known mechanisms responsible for the formation of various types of senescence, describes the features of senescence-related cardiac damage, and provides a detailed description of biologically active compounds and drugs with senolytic (apoptosis activators) and/or senostatic (SASP inhibitors) activity.

About the Authors

S. A. Kryzhanovskii
Federal research center for innovator and emerging biomedical and pharmaceutical technologies
Russian Federation

Sergey A. Kryzhanovskii, PhD, Dr. Sci. (Med.), Head of Laboratory of Circulation Pharmacology 

Moscow



M. B. Vititnova
Federal research center for innovator and emerging biomedical and pharmaceutical technologies
Russian Federation

Marina B. Vititnova, PhD, Cand. Sci. (Biology), Leading Researcher of Laboratory of Circulation Pharmacology 

Moscow



References

1. Vogt CI Untersuchungen über die Entwicklungsgeschichte der Geburtshelferkröte (Alytes obstetricans). Verag van Jent&Gassmann, 1842. – 134 p.

2. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972 Aug;26(4):239-57. doi: 10.1038/bjc.1972.33.

3. Tang D, Kang R, Berghe TV, et al. The molecular machinery of regulated cell death. Cell Res. 2019 May;29(5):347-364. doi: 10.1038/s41422-019-0164-5.

4. Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol. 1995 Jan;146(1):3-15.

5. Trump BF, Berezesky IK, Chang SH, Phelps PC. The pathways of cell death: oncosis, apoptosis, and necrosis. Toxicol Pathol. 1997 Jan-Feb;25(1):82-8. doi: 10.1177/019262339702500116.

6. Gujral JS, Knight TR, Farhood A, et al. Mode of cell death after acetaminophen overdose in mice: apoptosis or oncotic necrosis? Toxicol Sci. 2002 Jun;67(2):322-8. doi: 10.1093/toxsci/67.2.322.

7. Fuchs Y, Steller H. Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nat Rev Mol Cell Biol. 2015 Jun;16(6):329-44. doi: 10.1038/nrm3999.

8. Yamada K, Yoshida K. Mechanical insights into the regulation of programmed cell death by p53 via mitochondria. Biochim Biophys Acta Mol Cell Res. 2019 May;1866(5):839-848. doi: 10.1016/j.bbamcr.2019.02.009.

9. Santagostino SF, Assenmacher CA, Tarrant JC, et al. Mechanisms of Regulated Cell Death: Current Perspectives. Vet Pathol. 2021 Jul;58(4):596-623. doi: 10.1177/03009858211005537.

10. Liao M, Qin R, Huang W, et al. Targeting regulated cell death (RCD) with small-molecule compounds in triple-negative breast cancer: a revisited perspective from molecular mechanisms to targeted therapies. J Hematol Oncol. 2022 Apr 12;15(1):44. doi: 10.1186/s13045-022-01260-0.

11. Wang E. Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. Cancer Res. 1995 Jun 1;55(11):2284-92.

12. Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell. 2016 Jun;15(3):428-35. doi: 10.1111/acel.12445.

13. Dookun E, Passos JF, Arthur HM, Richardson GD. Therapeutic Potential of Senolytics in Cardiovascular Disease. Cardiovasc Drugs Ther. 2022 Feb;36(1):187-196. doi: 10.1007/s10557-020-07075-w.

14. Suda M, Paul KH, Minamino T, et al. Senescent Cells: A Therapeutic Target in Cardiovascular Diseases. Cells. 2023 May 2;12(9):1296. doi: 10.3390/cells12091296.

15. Kirkland JL, Tchkonia T, Zhu Y, et al. The Clinical Potential of Senolytic Drugs. J Am Geriatr Soc. 2017 Oct;65(10):2297-2301. doi: 10.1111/jgs.14969.

16. Zhu Y, Doornebal EJ, Pirtskhalava T, Giorgadze N, Wentworth M, Fuhrmann-Stroissnigg H, Niedernhofer LJ, Robbins PD, Tchkonia T, Kirkland JL. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY). 2017 Mar 8;9(3):955-963. doi: 10.18632/aging.101202.

17. Weissman A. Essays upon heredity and kindred biological problems. Oxford: Clarendon press., 1891. – 471 p. 12.

18. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961 Dec;25:585-621. doi: 10.1016/0014-4827(61)90192-6.

19. Оловников А.М. Принцип маргинотомии в матричном синтезе полинуклеотидов. Доклады Академии наук СССР. 1971;201(6):1496-9.

20. [Olovnikov AM. Principle of marginotomy in template synthesis of polynucleotides. Dokl Akad Nauk SSSR. 1971;201(6):1496-9. (In Russ.)].

21. de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005 Sep 15;19(18):2100-10. doi: 10.1101/gad.1346005.

22. Griffith JD, Comeau L, Rosenfield S, et al. Mammalian telomeres end in a large duplex loop. Cell. 1999 May 14;97(4):503-14. doi: 10.1016/s0092-8674(00)80760-6.

23. Regulski MJ. Cellular Senescence: What, Why, and How. Wounds. 2017 Jun;29(6):168-174.

24. Dodig S, Čepelak I, Pavić I. Hallmarks of senescence and aging. Biochem Med (Zagreb). 2019 Oct 15;29(3):030501. doi: 10.11613/BM.2019.030501.

25. Yanagi S, Tsubouchi H, Miura A, et al. The Impacts of Cellular Senescence in Elderly Pneumonia and in Age-Related Lung Diseases That Increase the Risk of Respiratory Infections. Int J Mol Sci. 2017 Feb 25;18(3):503. doi: 10.3390/ijms18030503.

26. Parrinello S, Samper E, Krtolica A, et al. Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol. 2003 Aug;5(8):741-7. doi: 10.1038/ncb1024. ].

27. Naka K, Tachibana A, Ikeda K, Motoyama N. Stress-induced premature senescence in hTERT-expressing ataxia telangiectasia fibroblasts. J Biol Chem. 2004 Jan 16;279(3):2030-7. doi: 10.1074/jbc.M309457200.

28. Coppé JP, Kauser K, Campisi J, Beauséjour CM. Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J Biol Chem. 2006 Oct 6;281(40):29568-74. doi: 10.1074/jbc.M603307200.

29. 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.

30. Acosta JC, Banito A, Wuestefeld T, et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol. 2013 Aug;15(8):978-90. doi: 10.1038/ncb2784.

31. Coppé JP, Patil CK, Rodier F, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008 Dec 2;6(12):2853-68. doi: 10.1371/journal.pbio.0060301.

32. Childs BG, Baker DJ, Kirkland JL, et al. Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep. 2014 Nov;15(11):1139-53. doi: 10.15252/embr.201439245.

33. Seluanov A, Gorbunova V, Falcovitz A, et al. Change of the death pathway in senescent human fibroblasts in response to DNA damage is caused by an inability to stabilize p53. Mol Cell Biol. 2001 Mar;21(5):1552-64. doi: 10.1128/MCB.21.5.1552-1564.2001.

34. Yosef R, Pilpel N, Tokarsky-Amiel R, et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun. 2016 Apr 6;7:11190. doi: 10.1038/ncomms11190.

35. Paez-Ribes M, González-Gualda E, Doherty GJ, Muñoz-Espín D. Targeting senescent cells in translational medicine. EMBO Mol Med. 2019 Dec;11(12):e10234. doi: 10.15252/emmm.201810234.

36. d'Adda di Fagagna F. Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer. 2008 Jul;8(7):512-22. doi: 10.1038/nrc2440.

37. Baar MP, Brandt RMC, Putavet DA, et al. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell. 2017 Mar 23;169(1):132-147.e16. doi: 10.1016/j.cell.2017.02.031.

38. Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013;75:685-705. doi: 10.1146/annurev-physiol-030212-183653.

39. Tran D, Bergholz J, Zhang H, et al. Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence. Aging Cell. 2014 Aug;13(4):669-78. doi: 10.1111/acel.12219.

40. Mehdizadeh M, Aguilar M, Thorin E, et al. The role of cellular senescence in cardiac disease: basic biology and clinical relevance. Nat Rev Cardiol. 2022 Apr;19(4):250-264. doi: 10.1038/s41569-021-00624-2.

41. Deschênes-Simard X, Gaumont-Leclerc MF, Bourdeau V, et al. Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation. Genes Dev. 2013 Apr 15;27(8):900-15. doi: 10.1101/gad.203984.112.

42. Ito T, Yagi S, Yamakuchi M. MicroRNA-34a regulation of endothelial senescence. Biochem Biophys Res Commun. 2010 Aug 6;398(4):735-40. doi: 10.1016/j.bbrc.2010.07.012.

43. Du WW, Li X, Li T, et al. The microRNA miR-17-3p inhibits mouse cardiac fibroblast senescence by targeting Par4. J Cell Sci. 2015 Jan 15;128(2):293-304. doi: 10.1242/jcs.158360.

44. Al-Khalaf HH, Aboussekhra A. p16INK4A induces senescence and inhibits EMT through microRNA-141/microRNA-146b-5p-dependent repression of AUF1. Mol Carcinog. 2017 Mar;56(3):985-999. doi: 10.1002/mc.22564.

45. Kurz DJ, Decary S, Hong Y, Erusalimsky JD. Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci. 2000 Oct;113 ( Pt 20):3613-22. doi: 10.1242/jcs.113.20.3613.

46. Lee BY, Han JA, Im JS, et al. Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell. 2006 Apr;5(2):187-95. doi: 10.1111/j.1474-9726.2006.00199.x.

47. Pinto AR, Ilinykh A, Ivey MJ, et al. Revisiting Cardiac Cellular Composition. Circ Res. 2016 Feb 5;118(3):400-9. doi: 10.1161/CIRCRESAHA.115.307778.

48. Zhou P, Pu WT. Recounting Cardiac Cellular Composition. Circ Res. 2016 Feb 5;118(3):368-70. doi: 10.1161/CIRCRESAHA.116.308139.

49. Bergmann O, Bhardwaj RD, Bernard S, et al. Evidence for cardiomyocyte renewal in humans. Science. 2009 Apr 3;324(5923):98-102. doi: 10.1126/science.1164680.

50. Anderson R, Lagnado A, Maggiorani D, et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 2019 Mar 1;38(5):e100492. doi: 10.15252/embj.2018100492.

51. Mitry MA, Laurent D, Keith BL, et al. Accelerated cardiomyocyte senescence contributes to late-onset doxorubicin-induced cardiotoxicity. Am J Physiol Cell Physiol. 2020 Feb 1;318(2):C380-C391. doi: 10.1152/ajpcell.00073.2019.

52. Sweeney M, Cook SA, Gil J. Therapeutic opportunities for senolysis in cardiovascular disease. FEBS J. 2023 Mar;290(5):1235-1255. doi: 10.1111/febs.16351.

53. Hoshino A, Mita Y, Okawa Y, et al. Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart. Nat Commun. 2013;4:2308. doi: 10.1038/ncomms3308.

54. Chang ZS, Xia JB, Wu HY, et al. Forkhead box O3 protects the heart against paraquat-induced aging-associated phenotypes by upregulating the expression of antioxidant enzymes. Aging Cell. 2019 Oct;18(5):e12990. doi: 10.1111/acel.12990.

55. Nacarelli T, Azar A, Sell C. Mitochondrial stress induces cellular senescence in an mTORC1-dependent manner. Free Radic Biol Med. 2016 Jun;95:133-54. doi: 10.1016/j.freeradbiomed.2016.03.008.

56. Bueno M, Papazoglou A, Valenzi E, et al. Mitochondria, Aging, and Cellular Senescence: Implications for Scleroderma. Curr Rheumatol Rep. 2020 Jun 19;22(8):37. doi: 10.1007/s11926-020-00920-9.

57. Chapman J, Fielder E, Passos JF. Mitochondrial dysfunction and cell senescence: deciphering a complex relationship. FEBS Lett. 2019 Jul;593(13):1566-1579. doi: 10.1002/1873-3468.13498.

58. El-Nachef D, Oyama K, Wu YY, et al. Repressive histone methylation regulates cardiac myocyte cell cycle exit. J Mol Cell Cardiol. 2018 Aug;121:1-12. doi: 10.1016/j.yjmcc.2018.05.013.

59. Cui S, Xue L, Yang F, et al. Postinfarction Hearts Are Protected by Premature Senescent Cardiomyocytes Via GATA 4-Dependent CCN 1 Secretion. J Am Heart Assoc. 2018 Sep 18;7(18):e009111. doi: 10.1161/JAHA.118.009111.

60. Gude NA, Broughton KM, Firouzi F, Sussman MA. Cardiac ageing: extrinsic and intrinsic factors in cellular renewal and senescence. Nat Rev Cardiol. 2018 Sep;15(9):523-542. doi: 10.1038/s41569-018-0061-5.

61. Zhu F, Li Y, Zhang J, et al. Senescent cardiac fibroblast is critical for cardiac fibrosis after myocardial infarction. PLoS One. 2013 Sep 11;8(9):e74535. doi: 10.1371/journal.pone.0074535.

62. Walaszczyk A, Dookun E, Redgrave R, et al. Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction. Aging Cell. 2019 Jun;18(3):e12945. doi: 10.1111/acel.12945.

63. Nishimura A, Shimauchi T, Tanaka T, et al. Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence. Sci Signal. 2018 Nov 13;11(556):eaat5185. doi: 10.1126/scisignal.aat5185.

64. Chouchani ET, Pell VR, Gaude E, et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 2014 Nov 20;515(7527):431-435. doi: 10.1038/nature13909.

65. Dookun E, Walaszczyk A, Redgrave R, et al. Clearance of senescent cells during cardiac ischemia-reperfusion injury improves recovery. Aging Cell. 2020 Oct;19(10):e13249. doi: 10.1111/acel.13249.

66. Redgrave R, Dookun E, Booth L, et al. Senescent cardiomyocytes contribute to cardiac dysfunction following myocardial infarction. Res Sq [Preprint]. 2023 Apr 10:rs.3.rs-2776501. doi: 10.21203/rs.3.rs-2776501/v1. Update in: NPJ Aging. 2023 Jun 14;9(1):15. doi: 10.1038/s41514-023-00113-5.

67. Meyer K, Hodwin B, Ramanujam D, et al. Essential Role for Premature Senescence of Myofibroblasts in Myocardial Fibrosis. J Am Coll Cardiol. 2016 May 3;67(17):2018-28. doi: 10.1016/j.jacc.2016.02.047.

68. Sawaki D, Czibik G, Pini M, et al. Visceral Adipose Tissue Drives Cardiac Aging Through Modulation of Fibroblast Senescence by Osteopontin Production. Circulation. 2018 Aug 21;138(8):809-822. doi: 10.1161/CIRCULATIONAHA.117.031358.

69. Sokolova M, Vinge LE, Alfsnes K, et al. Palmitate promotes inflammatory responses and cellular senescence in cardiac fibroblasts. Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Feb;1862(2):234-245. doi: 10.1016/j.bbalip.2016.11.003.

70. Lyu G, Guan Y, Zhang C, et al. TGF-β signaling alters H4K20me3 status via miR-29 and contributes to cellular senescence and cardiac aging. Nat Commun. 2018 Jul 2;9(1):2560. doi: 10.1038/s41467-018-04994-z.

71. Li WQ, Tan SL, Li XH, et al. Calcitonin gene-related peptide inhibits the cardiac fibroblasts senescence in cardiac fibrosis via up-regulating klotho expression. Eur J Pharmacol. 2019 Jan 15;843:96-103. doi: 10.1016/j.ejphar.2018.10.023.

72. Jazbutyte V, Fiedler J, Kneitz S, et al. MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart. Age (Dordr). 2013 Jun;35(3):747-62. doi: 10.1007/s11357-012-9407-9.

73. Bilsland AE, Revie J, Keith W. MicroRNA and senescence: the senectome, integration and distributed control. Crit Rev Oncog. 2013;18(4):373-90. doi: 10.1615/critrevoncog.2013007197.

74. Lin R, Rahtu-Korpela L, Magga J, et al. miR-1468-3p Promotes Aging-Related Cardiac Fibrosis. Mol Ther Nucleic Acids. 2020 Jun 5;20:589-605. doi: 10.1016/j.omtn.2020.04.001.

75. Tijsen AJ, van der Made I, van den Hoogenhof MM, et al. The microRNA-15 family inhibits the TGFβ-pathway in the heart. Cardiovasc Res. 2014 Oct 1;104(1):61-71. doi: 10.1093/cvr/cvu184.

76. Huang ZP, Wang DZ. miR-22 in Smooth Muscle Cells: A Potential Therapy for Cardiovascular Disease. Circulation. 2018 Apr 24;137(17):1842-1845. doi: 10.1161/CIRCULATIONAHA.118.033042.

77. Rich MW, Bosner MS, Chung MK, et al. Is age an independent predictor of early and late mortality in patients with acute myocardial infarction? Am J Med. 1992 Jan;92(1):7-13. doi: 10.1016/0002-9343(92)90008-y.

78. Brodsky SV, Gealekman O, Chen J, et al. Prevention and reversal of premature endothelial cell senescence and vasculopathy in obesity-induced diabetes by ebselen. Circ Res. 2004 Feb 20;94(3):377-84. doi: 10.1161/01.RES.0000111802.09964.EF.

79. Qureshi AW, Altamimy R, El Habhab A, et al. Ageing enhances the shedding of splenocyte microvesicles with endothelial pro-senescent effect that is prevented by a short-term intake of omega-3 PUFA EPA:DHA 6:1. Biochem Pharmacol. 2020 Mar;173:113734. doi: 10.1016/j.bcp.2019.113734.

80. Abbas M, Jesel L, Auger C, et al. Endothelial Microparticles From Acute Coronary Syndrome Patients Induce Premature Coronary Artery Endothelial Cell Aging and Thrombogenicity: Role of the Ang II/AT1 Receptor/NADPH Oxidase-Mediated Activation of MAPKs and PI3-Kinase Pathways. Circulation. 2017 Jan 17;135(3):280-296. doi: 10.1161/CIRCULATIONAHA.116.017513.

81. Ota H, Takehara N, Aonuma T, et al. Association between microalbuminuria predicting in-stent restenosis after myocardial infarction and cellular senescence of endothelial progenitor cells. PLoS One. 2015 Apr 13;10(4):e0123733. doi: 10.1371/journal.pone.0123733.

82. Eisen A, Ruff CT, Braunwald E, et al. Sudden Cardiac Death in Patients With Atrial Fibrillation: Insights From the ENGAGE AF-TIMI 48 Trial. J Am Heart Assoc. 2016 Jul 8;5(7):e003735. doi: 10.1161/JAHA.116.003735.

83. Virani SS, Alonso A, Aparicio HJ, et al. Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. Circulation. 2021 Feb 23;143(8):e254-e743. doi: 10.1161/CIR.0000000000000950.

84. Xie J, Chen Y, Hu C, et al. Premature senescence of cardiac fibroblasts and atrial fibrosis in patients with atrial fibrillation. Oncotarget. 2017 Aug 3;8(35):57981-57990. doi: 10.18632/oncotarget.19853.

85. Denil SL, Rietzschel ER, De Buyzere ML, et al. On cross-sectional associations of leukocyte telomere length with cardiac systolic, diastolic and vascular function: the Asklepios study. PLoS One. 2014 Dec 15;9(12):e115071. doi: 10.1371/journal.pone.0115071.

86. Carlquist JF, Knight S, Cawthon RM, et al. Shortened telomere length is associated with paroxysmal atrial fibrillation among cardiovascular patients enrolled in the Intermountain Heart Collaborative Study. Heart Rhythm. 2016 Jan;13(1):21-7. doi: 10.1016/j.hrthm.2015.07.032.

87. Sha Z, Hou T, Zhou T, et al. Causal relationship between atrial fibrillation and leukocyte telomere length: A two sample, bidirectional Mendelian randomization study. Front Cardiovasc Med. 2023 Feb 15;10:1093255. doi: 10.3389/fcvm.2023.1093255.

88. Jesel L, Abbas M, Toti F, et al. Microparticles in atrial fibrillation: a link between cell activation or apoptosis, tissue remodelling and thrombogenicity. Int J Cardiol. 2013 Sep 30;168(2):660-9. doi: 10.1016/j.ijcard.2013.03.031.

89. Burger D, Kwart DG, Montezano AC, et al. Microparticles induce cell cycle arrest through redox-sensitive processes in endothelial cells: implications in vascular senescence. J Am Heart Assoc. 2012 Jun;1(3):e001842. doi: 10.1161/JAHA.112.001842.

90. Morel O, Toti F, Hugel B, et al. Procoagulant microparticles: disrupting the vascular homeostasis equation? Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2594-604. doi: 10.1161/01.ATV.0000246775.14471.26.

91. Hasan H, Park SH, Auger C, et al. Thrombin Induces Angiotensin II-Mediated Senescence in Atrial Endothelial Cells: Impact on Pro-Remodeling Patterns. J Clin Med. 2019 Oct 1;8(10):1570. doi: 10.3390/jcm8101570.

92. Steinberg SF. The cardiovascular actions of protease-activated receptors. Mol Pharmacol. 2005 Jan;67(1):2-11. doi: 10.1124/mol.104.003103.

93. Pawlinski R, Tencati M, Hampton CR, et al. Protease-activated receptor-1 contributes to cardiac remodeling and hypertrophy. Circulation. 2007 Nov 13;116(20):2298-306. doi: 10.1161/CIRCULATIONAHA.107.692764.

94. Jumeau C, Rupin A, Chieng-Yane P, et al. Direct Thrombin Inhibitors Prevent Left Atrial Remodeling Associated With Heart Failure in Rats. JACC Basic Transl Sci. 2016 Jul 13;1(5):328-339. doi: 10.1016/j.jacbts.2016.05.002.

95. Vasileiou PVS, Evangelou K, Vlasis K, et al. Mitochondrial Homeostasis and Cellular Senescence. Cells. 2019 Jul 6;8(7):686. doi: 10.3390/cells8070686.

96. Emelyanova L, Ashary Z, Cosic M, et al. Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation. Am J Physiol Heart Circ Physiol. 2016 Jul 1;311(1):H54-63. doi: 10.1152/ajpheart.00699.2015.

97. Montaigne D, Marechal X, Lefebvre P, et al. Mitochondrial dysfunction as an arrhythmogenic substrate: a translational proof-of-concept study in patients with metabolic syndrome in whom post-operative atrial fibrillation develops. J Am Coll Cardiol. 2013 Oct 15;62(16):1466-73. doi: 10.1016/j.jacc.2013.03.061.

98. Triana-Martínez F, Picallos-Rabina P, Da Silva-Álvarez S, et al. Identification and characterization of Cardiac Glycosides as senolytic compounds. Nat Commun. 2019 Oct 21;10(1):4731. doi: 10.1038/s41467-019-12888-x. Erratum in: Nat Commun. 2020 Sep 16;11(1):4771. doi: 10.1038/s41467-020-18714-z.

99. Merner ND, Hodgkinson KA, Haywood AF, et al. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet. 2008 Apr;82(4):809-21. doi: 10.1016/j.ajhg.2008.01.010.

100. Rouhi L, Cheedipudi SM, Chen SN, et al. Haploinsufficiency of Tmem43 in cardiac myocytes activates the DNA damage response pathway leading to a late-onset senescence-associated pro-fibrotic cardiomyopathy. Cardiovasc Res. 2021 Sep 28;117(11):2377-2394. doi: 10.1093/cvr/cvaa300.

101. Abdelfatah N, Chen R, Duff HJ, et al. Characterization of a Unique Form of Arrhythmic Cardiomyopathy Caused by Recessive Mutation in LEMD2. JACC Basic Transl Sci. 2019 Apr 29;4(2):204-221. doi: 10.1016/j.jacbts.2018.12.001.

102. .

103. Maejima Y, Adachi S, Ito H, et al. Induction of premature senescence in cardiomyocytes by doxorubicin as a novel mechanism of myocardial damage. Aging Cell. 2008 Mar;7(2):125-36. doi: 10.1111/j.1474-9726.2007.00358.x.

104. Spallarossa P, Altieri P, Aloi C, et al. Doxorubicin induces senescence or apoptosis in rat neonatal cardiomyocytes by regulating the expression levels of the telomere binding factors 1 and 2. Am J Physiol Heart Circ Physiol. 2009 Dec;297(6):H2169-81. doi: 10.1152/ajpheart.00068.2009.

105. Li D, Li Y, Ding H, et al. Cellular Senescence in Cardiovascular Diseases: From Pathogenesis to Therapeutic Challenges. J Cardiovasc Dev Dis. 2023 Oct 23;10(10):439. doi: 10.3390/jcdd10100439.

106. Osorio JM, Espinoza-Pérez C, Rimassa-Taré C, et al. Senescent cardiac fibroblasts: A key role in cardiac fibrosis. Biochim Biophys Acta Mol Basis Dis. 2023 Apr;1869(4):166642. doi: 10.1016/j.bbadis.2023.166642.

107. Hu C, Zhang X, Teng T, et al. Cellular Senescence in Cardiovascular Diseases: A Systematic Review. Aging Dis. 2022 Feb 1;13(1):103-128. doi: 10.14336/AD.2021.0927.

108. Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015 Aug;14(4):644-58. doi: 10.1111/acel.12344.

109. Wissler Gerdes EO, Zhu Y, Tchkonia T, Kirkland JL. Discovery, development, and future application of senolytics: theories and predictions. FEBS J. 2020 Jun;287(12):2418-2427. doi: 10.1111/febs.15264.

110. Chaib S, Tchkonia T, Kirkland JL. Cellular senescence and senolytics: the path to the clinic. Nat Med. 2022 Aug;28(8):1556-1568. doi: 10.1038/s41591-022-01923-y.

111. Roos CM, Zhang B, Palmer AK, et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell. 2016 Oct;15(5):973-7. doi: 10.1111/acel.12458.

112. Childs BG, Baker DJ, Wijshake T, et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science. 2016 Oct 28;354(6311):472-477. doi: 10.1126/science.aaf6659.

113. Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011 Nov 2;479(7372):232-6. doi: 10.1038/nature10600.

114. Chang J, Wang Y, Shao L, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med. 2016 Jan;22(1):78-83. doi: 10.1038/nm.4010.

115. Lee JR, Park BW, Park JH, et al. Local delivery of a senolytic drug in ischemia and reperfusion-injured heart attenuates cardiac remodeling and restores impaired cardiac function. Acta Biomater. 2021 Nov;135:520-533. doi: 10.1016/j.actbio.2021.08.028.

116. Wilson WH, O'Connor OA, Czuczman MS, et al. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol. 2010 Dec;11(12):1149-59. doi: 10.1016/S1470-2045(10)70261-8.

117. Sellarés J, Rojas M. Quercetin in Idiopathic Pulmonary Fibrosis: Another Brick in the Senolytic Wall. Am J Respir Cell Mol Biol. 2019 Jan;60(1):3-4. doi: 10.1165/rcmb.2018-0267ED.

118. Shao Z, Wang B, Shi Y, et al. Senolytic agent Quercetin ameliorates intervertebral disc degeneration via the Nrf2/NF-κB axis. Osteoarthritis Cartilage. 2021 Mar;29(3):413-422. doi: 10.1016/j.joca.2020.11.006.

119. Xing X, Tang Q, Zou J, et al. Bone-targeted delivery of senolytics to eliminate senescent cells increases bone formation in senile osteoporosis. Acta Biomater. 2023 Feb;157:352-366. doi: 10.1016/j.actbio.2022.11.056.

120. .

121. Granato M, Rizzello C, Gilardini Montani MS, et al. Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways. J Nutr Biochem. 2017 Mar;41:124-136. doi: 10.1016/j.jnutbio.2016.12.011.

122. Montero JC, Seoane S, Ocaña A, Pandiella A. Inhibition of SRC family kinases and receptor tyrosine kinases by dasatinib: possible combinations in solid tumors. Clin Cancer Res. 2011 Sep 1;17(17):5546-52. doi: 10.1158/1078-0432.CCR-10-2616.

123. Vicinanza C, Aquila I, Scalise M, et al. Adult cardiac stem cells are multipotent and robustly myogenic: c-kit expression is necessary but not sufficient for their identification. Cell Death Differ. 2017 Dec;24(12):2101-2116. doi: 10.1038/cdd.2017.130.

124. Lewis-McDougall FC, Ruchaya PJ, Domenjo-Vila E, et al. Aged-senescent cells contribute to impaired heart regeneration. Aging Cell. 2019 Jun;18(3):e12931. doi: 10.1111/acel.12931.

125. Sandstedt J, Jonsson M, Dellgren G, et al. Human C-kit+CD45- cardiac stem cells are heterogeneous and display both cardiac and endothelial commitment by single-cell qPCR analysis. Biochem Biophys Res Commun. 2014 Jan 3;443(1):234-8. doi: 10.1016/j.bbrc.2013.11.086.

126. Li T, Li S, Ma K, Kong J. Application potential of senolytics in clinical treatment. Biogerontology. 2024 Jun;25(3):379-398. doi: 10.1007/s10522-023-10084-5.

127. Lee HN, Jin HO, Park JA, et al. Heme oxygenase-1 determines the differential response of breast cancer and normal cells to piperlongumine. Mol Cells. 2015 Apr;38(4):327-35. doi: 10.14348/molcells.2015.2235.

128. Shan H, Li T, Zhang L, et al. Heme oxygenase-1 prevents heart against myocardial infarction by attenuating ischemic injury-induced cardiomyocytes senescence. EBioMedicine. 2019 Jan;39:59-68. doi: 10.1016/j.ebiom.2018.11.056.

129. Luo W, Wang Y, Yang H, et al. Heme oxygenase-1 ameliorates oxidative stress-induced endothelial senescence via regulating endothelial nitric oxide synthase activation and coupling. Aging (Albany NY). 2018 Jul 24;10(7):1722-1744. doi: 10.18632/aging.101506.

130. Fuhrmann-Stroissnigg H, Ling YY, Zhao J, et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat Commun. 2017 Sep 4;8(1):422. doi: 10.1038/s41467-017-00314-z.

131. Altieri DC, Stein GS, Lian JB, Languino LR. TRAP-1, the mitochondrial Hsp90. Biochim Biophys Acta. 2012 Mar;1823(3):767-73. doi: 10.1016/j.bbamcr.2011.08.007.

132. Guerrero A, Herranz N, Sun B, et al. Cardiac glycosides are broad-spectrum senolytics. Nat Metab. 2019 Nov;1(11):1074-1088. doi: 10.1038/s42255-019-0122-z.

133. Martin N, Soriani O, Bernard D. Cardiac Glycosides as Senolytic Compounds. Trends Mol Med. 2020 Mar;26(3):243-245. doi: 10.1016/j.molmed.2020.01.001.

134. Wakita M, Takahashi A, Sano O, et al. A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells. Nat Commun. 2020 Apr 22;11(1):1935. doi: 10.1038/s41467-020-15719-6.

135. Haynes SR, Dollard C, Winston F, et al. The bromodomain: a conserved sequence found in human, Drosophila and yeast proteins. Nucleic Acids Res. 1992 May 25;20(10):2603. doi: 10.1093/nar/20.10.2603.

136. Devaiah BN, Lewis BA, Cherman N, et al. BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain. Proc Natl Acad Sci U S A. 2012 May 1;109(18):6927-32. doi: 10.1073/pnas.1120422109.

137. Sims RJ 3rd, Mandal SS, Reinberg D. Recent highlights of RNA-polymerase-II-mediated transcription. Curr Opin Cell Biol. 2004 Jun;16(3):263-71. doi: 10.1016/j.ceb.2004.04.004.

138. Li X, Baek G, Ramanand SG, Sharp A, et al. BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer. Cell Rep. 2018 Jan 16;22(3):796-808. doi: 10.1016/j.celrep.2017.12.078.

139. Lu J, Qian Y, Altieri M, et al. Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. Chem Biol. 2015 Jun 18;22(6):755-63. doi: 10.1016/j.chembiol.2015.05.009.

140. Ozsvari B, Nuttall JR, Sotgia F, Lisanti MP. Azithromycin and Roxithromycin define a new family of «senolytic» drugs that target senescent human fibroblasts. Aging (Albany NY). 2018 Nov 14;10(11):3294-3307. doi: 10.18632/aging.101633.

141. Chae JB, Jang H, Son C, et al. Targeting senescent retinal pigment epithelial cells facilitates retinal regeneration in mouse models of age-related macular degeneration. Geroscience. 2021 Dec;43(6):2809-2833. doi: 10.1007/s11357-021-00457-4. Epub 2021 Oct 2. Erratum in: Geroscience. 2022 Jun;44(3):1885. doi: 10.1007/s11357-022-00523-5.

142. Yousefzadeh MJ, Zhu Y, McGowan SJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct;36:18-28. doi: 10.1016/j.ebiom.2018.09.015.

143. Bielak-Zmijewska A, Grabowska W, Ciolko A, et al. The Role of Curcumin in the Modulation of Ageing. Int J Mol Sci. 2019 Mar 12;20(5):1239. doi: 10.3390/ijms20051239.

144. Xu M, Tchkonia T, Ding H, et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc Natl Acad Sci U S A. 2015 Nov 17;112(46):E6301-10. doi: 10.1073/pnas.1515386112.

145. Lamming DW, Ye L, Sabatini DM, Baur JA. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J Clin Invest. 2013 Mar;123(3):980-9. doi: 10.1172/JCI64099.

146. 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 Jun;12(3):489-98. doi: 10.1111/acel.12075.

147. Luís C, Maduro AT, Pereira P, et al. Nutritional senolytics and senomorphics: Implications to immune cells metabolism and aging - from theory to practice. Front Nutr. 2022 Sep 8;9:958563. doi: 10.3389/fnut.2022.958563.

148. Budamagunta V, Manohar-Sindhu S, Yang Y, et al. Senescence-associated hyper-activation to inflammatory stimuli in vitro. Aging (Albany NY). 2021 Aug 10;13(15):19088-19107. doi: 10.18632/aging.203396.

149. Cayo A, Segovia R, Venturini W, et al. mTOR Activity and Autophagy in Senescent Cells, a Complex Partnership. Int J Mol Sci. 2021 Jul 29;22(15):8149. doi: 10.3390/ijms22158149.

150. Woo J, Shin S, Ji H, et al. Isatis tinctoria L. Leaf Extract Inhibits Replicative Senescence in Dermal Fibroblasts by Regulating mTOR-NF-κB-SASP Signaling. Nutrients. 2022 May 9;14(9):1979. doi: 10.3390/nu14091979.

151. Fernandes SE, Saini DK. The ERK-p38MAPK-STAT3 Signalling Axis Regulates iNOS Expression and Salmonella Infection in Senescent Cells. Front Cell Infect Microbiol. 2021 Oct 22;11:744013. doi: 10.3389/fcimb.2021.744013.

152. Tang N, Dong Y, Chen C, Zhao H. Anisodamine Maintains the Stability of Intervertebral Disc Tissue by Inhibiting the Senescence of Nucleus Pulposus Cells and Degradation of Extracellular Matrix via Interleukin-6/Janus Kinases/Signal Transducer and Activator of Transcription 3 Pathway. Front Pharmacol. 2020 Dec 15;11:519172. doi: 10.3389/fphar.2020.519172.

153. Ohtani N. The roles and mechanisms of senescence-associated secretory phenotype (SASP): can it be controlled by senolysis? Inflamm Regen. 2022 Apr 2;42(1):11. doi: 10.1186/s41232-022-00197-8.

154. Liu H, Wang F, Cao Y, et al. The multifaceted functions of cGAS. J Mol Cell Biol. 2022 Sep 15;14(5):mjac031. doi: 10.1093/jmcb/mjac031.

155. Shah PP, Donahue G, Otte GL, et al. Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev. 2013 Aug 15;27(16):1787-99. doi: 10.1101/gad.223834.113.

156. Takahashi A, Loo TM, Okada R, et al. Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells. Nat Commun. 2018 Mar 28;9(1):1249. doi: 10.1038/s41467-018-03555-8.

157. .

158. De Cecco M, Ito T, Petrashen AP, et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature. 2019 Feb;566(7742):73-78. doi: 10.1038/s41586-018-0784-9. Epub 2019 Feb 6. Erratum in: Nature. 2019 Aug;572(7767):E5. doi: 10.1038/s41586-019-1350-9.

159. Victorelli S, Salmonowicz H, Chapman J, et al. Apoptotic stress causes mtDNA release during senescence and drives the SASP. Nature. 2023 Oct;622(7983):627-636. doi: 10.1038/s41586-023-06621-4. Epub 2023 Oct 11. Erratum in: Nature. 2024 Jan;625(7995):E15. doi: 10.1038/s41586-023-07002-7.

160. Hayden MS, West AP, Ghosh S. NF-kappaB and the immune response. Oncogene. 2006 Oct 30;25(51):6758-80. doi: 10.1038/sj.onc.1209943.

161. Hayden MS, Ghosh S. Shared principles in NF-kappaB signaling. Cell. 2008 Feb 8;132(3):344-62. doi: 10.1016/j.cell.2008.01.020.

162. Furia B, Deng L, Wu K, et al. Enhancement of nuclear factor-kappa B acetylation by coactivator p300 and HIV-1 Tat proteins. J Biol Chem. 2002 Feb 15;277(7):4973-80. doi: 10.1074/jbc.M107848200.

163. Loi H, Kramar S, Laborde C, et al. Metformin Attenuates Postinfarction Myocardial Fibrosis and Inflammation in Mice. Int J Mol Sci. 2021 Aug 30;22(17):9393. doi: 10.3390/ijms22179393.

164. Kim YD, Park KG, Lee YS, et al. Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP. Diabetes. 2008 Feb;57(2):306-14. doi: 10.2337/db07-0381.

165. Kalender A, Selvaraj A, Kim SY, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 2010 May 5;11(5):390-401. doi: 10.1016/j.cmet.2010.03.014.

166. Ben Sahra I, Regazzetti C, Robert G, et al. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res. 2011 Jul 1;71(13):4366-72. doi: 10.1158/0008-5472.CAN-10-1769.

167. Granato M, Gilardini Montani MS, et al. Metformin triggers apoptosis in PEL cells and alters bortezomib-induced Unfolded Protein Response increasing its cytotoxicity and inhibiting KSHV lytic cycle activation. Cell Signal. 2017 Dec;40:239-247. doi: 10.1016/j.cellsig.2017.09.020.

168. Duan W, Zou H, Zang N, et al. Metformin increases bone marrow adipose tissue by promoting mesenchymal stromal cells apoptosis. Aging (Albany NY). 2023 Jan 14;15(2):542-552. doi: 10.18632/aging.204486.

169. Anisimov VN, Berstein LM, Egormin PA, et al. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol. 2005 Aug-Sep;40(8-9):685-93. doi: 10.1016/j.exger.2005.07.007.

170. Anisimov VN, Berstein LM, Egormin PA, et al. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle. 2008 Sep 1;7(17):2769-73. doi: 10.4161/cc.7.17.6625.

171. Hartman ML, Talar B, Sztiller-Sikorska M, et al. Parthenolide induces MITF-M downregulation and senescence in patient-derived MITF-M(high) melanoma cell populations. Oncotarget. 2016 Feb 23;7(8):9026-40. doi: 10.18632/oncotarget.7030.

172. Adler AS, Sinha S, Kawahara TL, et al. Motif module map reveals enforcement of aging by continual NF-kappaB activity. Genes Dev. 2007 Dec 15;21(24):3244-57. doi: 10.1101/gad.1588507.

173. Vellai T, Takacs-Vellai K, Zhang Y, et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature. 2003 Dec 11;426(6967):620. doi: 10.1038/426620a.

174. Vézina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo). 1975 Oct;28(10):721-6. doi: 10.7164/antibiotics.28.721.

175. .

176. Brattström C, Säwe J, Tydén G, et al. Kinetics and dynamics of single oral doses of sirolimus in sixteen renal transplant recipients. Ther Drug Monit. 1997 Aug;19(4):397-406. doi: 10.1097/00007691-199708000-00007.

177. Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009 Jul 16;460(7253):392-5. doi: 10.1038/nature08221.

178. Weichhart T. mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review. Gerontology. 2018;64(2):127-134. doi: 10.1159/000484629.

179. Caron A, Richard D, Laplante M. The Roles of mTOR Complexes in Lipid Metabolism. Annu Rev Nutr. 2015;35:321-48. doi: 10.1146/annurev-nutr-071714-034355.

180. Lamming DW. Inhibition of the Mechanistic Target of Rapamycin (mTOR)-Rapamycin and Beyond. Cold Spring Harb Perspect Med. 2016 May 2;6(5):a025924. doi: 10.1101/cshperspect.a025924.

181. Arriola Apelo SI, Pumper CP, Baar EL, et al. Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice. J Gerontol A Biol Sci Med Sci. 2016 Jul;71(7):876-81. doi: 10.1093/gerona/glw064.

182. Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell. 2006 Apr 21;22(2):159-68. doi: 10.1016/j.molcel.2006.03.029.

183. Wilkinson JE, Burmeister L, Brooks SV, et al. Rapamycin slows aging in mice. Aging Cell. 2012 Aug;11(4):675-82. doi: 10.1111/j.1474-9726.2012.00832.x.

184. Flynn JM, O'Leary MN, Zambataro CA, et al. Late-life rapamycin treatment reverses age-related heart dysfunction. Aging Cell. 2013 Oct;12(5):851-62. doi: 10.1111/acel.12109.

185. Neff F, Flores-Dominguez D, Ryan DP, et al. Rapamycin extends murine lifespan but has limited effects on aging. J Clin Invest. 2013 Aug;123(8):3272-91. doi: 10.1172/JCI67674.

186. Halloran J, Hussong SA, Burbank R, et al. Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. Neuroscience. 2012 Oct 25;223:102-13. doi: 10.1016/j.neuroscience.2012.06.054.

187. Chiao YA, Kolwicz SC, Basisty N, et al. Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts. Aging (Albany NY). 2016 Feb;8(2):314-27. doi: 10.18632/aging.100881.

188. Blagosklonny MV. From rapalogs to anti-aging formula. Oncotarget. 2017 May 30;8(22):35492-35507. doi: 10.18632/oncotarget.18033.

189. Li K, Shen X, Qiu H, et al. S6K1/S6 axis-regulated lymphocyte activation is important for adaptive immune response of Nile tilapia. Fish Shellfish Immunol. 2020 Nov;106:1120-1130. doi: 10.1016/j.fsi.2020.09.031.

190. Xiong Y, Fru MF, Yu Y, et al. Long term exposure to L-arginine accelerates endothelial cell senescence through arginase-II and S6K1 signaling. Aging (Albany NY). 2014 May;6(5):369-79. doi: 10.18632/aging.100663.

191. Selman C, Tullet JM, Wieser D, et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science. 2009 Oct 2;326(5949):140-4. doi: 10.1126/science.1177221.

192. Yi J, Luo J. SIRT1 and p53, effect on cancer, senescence and beyond. Biochim Biophys Acta. 2010 Aug;1804(8):1684-9. doi: 10.1016/j.bbapap.2010.05.002.

193. Tong C, Morrison A, Mattison S, et al. Impaired SIRT1 nucleocytoplasmic shuttling in the senescent heart during ischemic stress. FASEB J. 2013 Nov;27(11):4332-42. doi: 10.1096/fj.12-216473.

194. Feng H, Mou SQ, Li WJ, et al. Resveratrol Inhibits Ischemia-Induced Myocardial Senescence Signals and NLRP3 Inflammasome Activation. Oxid Med Cell Longev. 2020 Aug 25;2020:2647807. doi: 10.1155/2020/2647807.

195. Truong VL, Jun M, Jeong WS. Role of resveratrol in regulation of cellular defense systems against oxidative stress. Biofactors. 2018 Jan;44(1):36-49. doi: 10.1002/biof.1399.

196. Liu B, Ghosh S, Yang X, et al. Resveratrol rescues SIRT1-dependent adult stem cell decline and alleviates progeroid features in laminopathy-based progeria. Cell Metab. 2012 Dec 5;16(6):738-50. doi: 10.1016/j.cmet.2012.11.007.

197. Zhang DZ, Jia MY, Wei HY, et al. Systematic review and meta-analysis of the interventional effects of resveratrol in a rat model of myocardial ischemia-reperfusion injury. Front Pharmacol. 2024 Jan 19;15:1301502. doi: 10.3389/fphar.2024.1301502.

198. Pacholec M, Bleasdale JE, Chrunyk B, et al. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem. 2010 Mar 12;285(11):8340-51. doi: 10.1074/jbc.M109.088682.

199. Cuyàs E, Verdura S, Llorach-Parés L, et al. Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation. Front Endocrinol (Lausanne). 2018 Nov 6;9:657. doi: 10.3389/fendo.2018.00657.

200. Hammarén HM, Virtanen AT, Raivola J, Silvennoinen O. The regulation of JAKs in cytokine signaling and its breakdown in disease. Cytokine. 2019 Jun;118:48-63. doi: 10.1016/j.cyto.2018.03.041.

201. Xu M, Tchkonia T, Kirkland JL. Perspective: Targeting the JAK/STAT pathway to fight age-related dysfunction. Pharmacol Res. 2016 Sep;111:152-154. doi: 10.1016/j.phrs.2016.05.015.

202. Ji T, Chen M, Sun W, et al. JAK-STAT signaling mediates the senescence of cartilage-derived stem/progenitor cells. J Mol Histol. 2022 Aug;53(4):635-643. doi: 10.1007/s10735-022-10086-6.

203. Griveau A, Wiel C, Ziegler DV, et al. The JAK1/2 inhibitor ruxolitinib delays premature aging phenotypes. Aging Cell. 2020 Apr;19(4):e13122. doi: 10.1111/acel.13122.

204. Schmitt CA. UnSASPing Senescence: Unmasking Tumor Suppression? Cancer Cell. 2018 Jul 9;34(1):6-8. doi: 10.1016/j.ccell.2018.06.009.

205. Georgilis A, Klotz S, Hanley CJ, et al. PTBP1-Mediated Alternative Splicing Regulates the Inflammatory Secretome and the Pro-tumorigenic Effects of Senescent Cells. Cancer Cell. 2018 Jul 9;34(1):85-102.e9. doi: 10.1016/j.ccell.2018.06.007.

206. Liu Z, Wang L, Welch JD, et al. Single-cell transcriptomics reconstructs fate conversion from fibroblast to cardiomyocyte. Nature. 2017 Nov 2;551(7678):100-104. doi: 10.1038/nature24454.

207. Herranz N, Gil J. Mechanisms and functions of cellular senescence. J Clin Invest. 2018 Apr 2;128(4):1238-1246. doi: 10.1172/JCI95148.

208. An S, Cho SY, Kang J, et al. Inhibition of 3-phosphoinositide-dependent protein kinase 1 (PDK1) can revert cellular senescence in human dermal fibroblasts. Proc Natl Acad Sci U S A. 2020 Dec 8;117(49):31535-31546. doi: 10.1073/pnas.1920338117.

209. Lapasset L, Milhavet O, Prieur A, et al. Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes Dev. 2011 Nov 1;25(21):2248-53. doi: 10.1101/gad.173922.111.

210. Paramos-de-Carvalho D, Jacinto A, Saúde L. The right time for senescence. Elife. 2021 Nov 10;10:e72449. doi: 10.7554/eLife.72449.


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Kryzhanovskii S.A., Vititnova M.B. Senesens. Heart. Senotherapy. Pharmacokinetics and Pharmacodynamics. 2024;(3):3-19. (In Russ.) https://doi.org/10.37489/2588-0519-2024-3-3-19. EDN: EZRHZW

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