REFERENCES
1. Cardiovascular diseases (CVDs). World Health Organization. 2021. Available from: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) [Last accessed on 22 Apr 2025].
2. Ageing and health. World Health Organization. 2024. Available from: https://www.who.int/news-room/fact-sheets/detail/ageing-and-health [Last accessed on 22 Apr 2025].
3. Austad SN. The geroscience hypothesis: is it possible to change the rate of aging? In: Sierra F, Kohanski R, editors. Advances in geroscience. Cham: Springer International Publishing; 2016. pp. 1-36.
4. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. 2023;186:243-78.
5. Abdellatif M, Rainer PP, Sedej S, Kroemer G. Hallmarks of cardiovascular ageing. Nat Rev Cardiol. 2023;20:754-77.
6. Sillen M, Declerck PJ. Targeting PAI-1 in cardiovascular disease: structural insights into PAI-1 functionality and inhibition. Front Cardiovasc Med. 2020;7:622473.
7. Loskutoff DJ, van Mourik JA, Erickson LA, Lawrence D. Detection of an unusually stable fibrinolytic inhibitor produced by bovine endothelial cells. Proc Natl Acad Sci USA. 1983;80:2956-60.
8. Eren M, Place AT, Thomas PM, Flevaris P, Miyata T, Vaughan DE. PAI-1 is a critical regulator of FGF23 homeostasis. Sci Adv. 2017;3:e1603259.
9. Gerenu G, Martisova E, Ferrero H, et al. Modulation of BDNF cleavage by plasminogen-activator inhibitor-1 contributes to Alzheimer's neuropathology and cognitive deficits. Biochim Biophys Acta Mol Basis Dis. 2017;1863:991-1001.
10. Cai D, Holm JM, Duignan IJ, et al. BDNF-mediated enhancement of inflammation and injury in the aging heart. Physiol Genomics. 2006;24:191-7.
11. Elzi DJ, Lai Y, Song M, Hakala K, Weintraub ST, Shiio Y. Plasminogen activator inhibitor 1-insulin-like growth factor binding protein 3 cascade regulates stress-induced senescence. Proc Natl Acad Sci USA. 2012;109:12052-7.
12. Wang H, Zhang Y, Heuckeroth RO. PAI-1 deficiency reduces liver fibrosis after bile duct ligation in mice through activation of tPA. FEBS Lett. 2007;581:3098-104.
13. Morrow GB, Whyte CS, Mutch NJ. A serpin with a finger in many PAIs: PAI-1’s central function in thromboinflammation and cardiovascular disease. Front Cardiovasc Med. 2021;8:653655.
14. Tjärnlund-Wolf A, Brogren H, Lo EH, Wang X. Plasminogen activator inhibitor-1 and thrombotic cerebrovascular diseases. Stroke. 2012;43:2833-9.
15. Rizzo MR, Ragno E, Barbieri M, et al. Elevated plasma activator inhibitor 1 is not related to insulin resistance and to gene polymorphism in healthy centenarians. Atherosclerosis. 2002;160:385-90.
16. Samad F, Loskutoff DJ. Tissue distribution and regulation of plasminogen activator inhibitor-1 in obese mice. Mol Med. 1996;2:568-82.
17. Eren M, Painter CA, Atkinson JB, Declerck PJ, Vaughan DE. Age-dependent spontaneous coronary arterial thrombosis in transgenic mice that express a stable form of human plasminogen activator inhibitor-1. Circulation. 2002;106:491-6.
18. Eren M, Gleaves LA, Atkinson JB, King LE, Declerck PJ, Vaughan DE. Reactive site-dependent phenotypic alterations in plasminogen activator inhibitor-1 transgenic mice. J Thromb Haemost. 2007;5:1500-8.
19. Yamamoto K, Takeshita K, Kojima T, Takamatsu J, Saito H. Aging and plasminogen activator inhibitor-1 (PAI-1) regulation: implication in the pathogenesis of thrombotic disorders in the elderly. Cardiovasc Res. 2005;66:276-85.
20. Laurent S, Boutouyrie P, Asmar R, et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension. 2001;37:1236-41.
21. Regnault V, Lacolley P, Laurent S. Arterial stiffness: from basic primers to integrative physiology. Annu Rev Physiol. 2024;86:99-121.
22. Lyle AN, Raaz U. Killing me unsoftly: causes and mechanisms of arterial stiffness. Arterioscler Thromb Vasc Biol. 2017;37:e1-11.
23. Hickson SS, Butlin M, Graves M, et al. The relationship of age with regional aortic stiffness and diameter. JACC Cardiovasc Imaging. 2010;3:1247-55.
24. Kawasaki T, Sasayama S, Yagi S, Asakawa T, Hirai T. Non-invasive assessment of the age related changes in stiffness of major branches of the human arteries. Cardiovasc Res. 1987;21:678-87.
25. Vatner SF, Zhang J, Vyzas C, Mishra K, Graham RM, Vatner DE. Vascular stiffness in aging and disease. Front Physiol. 2021;12:762437.
26. Chu CQ, Quan T. Fibroblast Yap/Taz signaling in extracellular matrix homeostasis and tissue fibrosis. J Clin Med. 2024;13:3358.
27. Ribeiro-Silva JC, Nolasco P, Krieger JE, Miyakawa AA. Dynamic crosstalk between vascular smooth muscle cells and the aged extracellular matrix. Int J Mol Sci. 2021;22:10175.
28. Klingberg F, Hinz B, White ES. The myofibroblast matrix: implications for tissue repair and fibrosis. J Pathol. 2013;229:298-309.
29. Kennelly PJ, Botham KM, McGuinness OP, Rodwell VW, Weil PA. Harper’s illustrated biochemistry, 32nd edition. 2023. Available from: https://archive.org/details/harpers-illustrated-biochemistry-thirty-second-edition-2023/mode/2up [Last accessed on 22 Apr 2025].
30. Kolpakov V, Gordon D, Kulik TJ. Nitric oxide-generating compounds inhibit total protein and collagen synthesis in cultured vascular smooth muscle cells. Circ Res. 1995;76:305-9.
31. Diebold I, Kraicun D, Bonello S, Görlach A. The ‘PAI-1 paradox’ in vascular remodelling. Thromb Haemost. 2008;100:984-91.
32. Zaman AK, French CJ, Schneider DJ, Sobel BE. A profibrotic effect of plasminogen activator inhibitor type-1 (PAI-1) in the heart. Exp Biol Med. 2009;234:246-54.
33. Lackie PM. Molecular portfolios: cells interacting with matrix in repairing airway epithelium: this editorial discusses the findings of the paper in this issue by Stevens et al. [3] pp. 1901-10. Clin Exp Allergy. 2008;38:1840-3.
34. Gramley F, Lorenzen J, Plisiene J, et al. Decreased plasminogen activator inhibitor and tissue metalloproteinase inhibitor expression may promote increased metalloproteinase activity with increasing duration of human atrial fibrillation. J Cardiovasc Electrophysiol. 2007;18:1076-82.
36. Kortlever RM, Nijwening JH, Bernards R. Transforming growth factor-beta requires its target plasminogen activator inhibitor-1 for cytostatic activity. J Biol Chem. 2008;283:24308-13.
37. Pedroja BS, Kang LE, Imas AO, Carmeliet P, Bernstein AM. Plasminogen activator inhibitor-1 regulates integrin αvβ3 expression and autocrine transforming growth factor β signaling. J Biol Chem. 2009;284:20708-17.
38. Boe AE, Eren M, Murphy SB, et al. Plasminogen activator inhibitor-1 antagonist TM5441 attenuates Nω-nitro-L-arginine methyl ester-induced hypertension and vascular senescence. Circulation. 2013;128:2318-24.
39. Garcia V, Park EJ, Siragusa M, et al. Unbiased proteomics identifies plasminogen activator inhibitor-1 as a negative regulator of endothelial nitric oxide synthase. Proc Natl Acad Sci USA. 2020;117:9497-507.
40. Khoukaz HB, Vadali M, Schoenherr A, et al. PAI-1 regulates the cytoskeleton and intrinsic stiffness of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2024;44:2191-203.
41. Matsushita H, Chang E, Glassford AJ, Cooke JP, Chiu CP, Tsao PS. eNOS activity is reduced in senescent human endothelial cells: preservation by hTERT immortalization. Circ Res. 2001;89:793-8.
42. Campisi J, d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8:729-40.
43. Han Y, Kim SY. Endothelial senescence in vascular diseases: current understanding and future opportunities in senotherapeutics. Exp Mol Med. 2023;55:1-12.
44. Bloom SI, Islam MT, Lesniewski LA, Donato AJ. Mechanisms and consequences of endothelial cell senescence. Nat Rev Cardiol. 2023;20:38-51.
45. Stefens SJM, van Vliet N, IJpma A, et al. Increased vascular smooth muscle cell senescence in aneurysmal Fibulin-4 mutant mice. NPJ Aging. 2024;10:31.
46. Gasek NS, Kuchel GA, Kirkland JL, Xu M. Strategies for targeting senescent cells in human disease. Nat Aging. 2021;1:870-9.
47. Burton DG, Matsubara H, Ikeda K. Pathophysiology of vascular calcification: pivotal role of cellular senescence in vascular smooth muscle cells. Exp Gerontol. 2010;45:819-24.
48. Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479:232-6.
49. Baker DJ, Childs BG, Durik M, et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016;530:184-9.
50. Zhang X, Pearsall VM, Carver CM, et al. Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance. Nat Commun. 2022;13:5671.
51. Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14:644-58.
52. Kirkland JL, Tchkonia T. Cellular senescence: a translational perspective. EBioMedicine. 2017;21:21-8.
53. Tao W, Yu Z, Han JJ. Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators. Cell Metab. 2024;36:1126-43.e5.
54. Vaughan DE, Rai R, Khan SS, Eren M, Ghosh AK. Plasminogen activator inhibitor-1 is a marker and a mediator of senescence. Arterioscler Thromb Vasc Biol. 2017;37:1446-52.
55. Kortlever RM, Higgins PJ, Bernards R. Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nat Cell Biol. 2006;8:877-84.
56. Cesari M, Pahor M, Incalzi RA. Plasminogen activator inhibitor-1 (PAI-1): a key factor linking fibrinolysis and age-related subclinical and clinical conditions. Cardiovasc Ther. 2010;28:e72-91.
57. Eren M, Boe AE, Klyachko EA, Vaughan DE. Role of plasminogen activator inhibitor-1 in senescence and aging. Semin Thromb Hemost. 2014;40:645-51.
58. Sillen M, Declerck PJ. A narrative review on plasminogen activator inhibitor-1 and its (patho)physiological role: to target or not to target?. Int J Mol Sci. 2021;22:2721.
59. Sun T, Ghosh AK, Eren M, Miyata T, Vaughan DE. PAI-1 contributes to homocysteine-induced cellular senescence. Cell Signal. 2019;64:109394.
60. Ghosh AK, Rai R, Park KE, et al. A small molecule inhibitor of PAI-1 protects against doxorubicin-induced cellular senescence. Oncotarget. 2016;7:72443-57.
61. Uryga AK, Grootaert MOJ, Garrido AM, et al. Telomere damage promotes vascular smooth muscle cell senescence and immune cell recruitment after vessel injury. Commun Biol. 2021;4:611.
62. Saggau C, Bacher P, Esser D, et al. Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases. Immunity. 2024;57:2416-32.e8.
63. Onorati A, Havas AP, Lin B, et al. Upregulation of PD-L1 in senescence and aging. Mol Cell Biol. 2022;42:e0017122.
64. Cho HJ, Hwang JA, Yang EJ, et al. Nintedanib induces senolytic effect via STAT3 inhibition. Cell Death Dis. 2022;13:760.
65. Xu M, Palmer AK, Ding H, et al. Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife. 2015;4:e12997.
66. 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 USA. 2015;112:E6301-10.
67. Wang TW, Johmura Y, Suzuki N, et al. Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes. Nature. 2022;611:358-64.
68. Suero-Abreu GA, Zanni MV, Neilan TG. Atherosclerosis with immune checkpoint inhibitor therapy: evidence, diagnosis, and management: JACC: CardioOncology state-of-the-art review. JACC CardioOncol. 2022;4:598-615.
69. Ibrahim AA, Fujimura T, Uno T, et al. Plasminogen activator inhibitor-1 promotes immune evasion in tumors by facilitating the expression of programmed cell death-ligand 1. Front Immunol. 2024;15:1365894.
70. Lin LL, Nayak B, Osmulski PA, et al. PAI-1 uncouples integrin-β1 from restrain by membrane-bound β-catenin to promote collagen fibril remodeling in obesity-related neoplasms. Cell Rep. 2024;43:114527.
71. Hendrikson J, Liu Y, Ng WH, et al. Ligand-mediated PAI-1 inhibition in a mouse model of peritoneal carcinomatosis. Cell Rep Med. 2022;3:100526.
72. Kortlever RM, Bernards R. Senescence, wound healing and cancer: the PAI-1 connection. Cell Cycle. 2006;5:2697-703.
73. Chibaya L, Snyder J, Ruscetti M. Senescence and the tumor-immune landscape: Implications for cancer immunotherapy. Semin Cancer Biol. 2022;86:827-45.
74. Lin LL, Kost ER, Lin CL, et al. PAI-1-dependent inactivation of SMAD4-modulated junction and adhesion complex in obese endometrial cancer. Cell Rep. 2020;33:108253.
75. Kubala MH, DeClerck YA. The plasminogen activator inhibitor-1 paradox in cancer: a mechanistic understanding. Cancer Metastasis Rev. 2019;38:483-92.
76. Bastard J, Piéroni L, Hainque B. Relationship between plasma plasminogen activator inhibitor 1 and insulin resistance. Diabetes Metab Res Rev. 2000;16:192-201.
77. Nordt TK, Sawa H, Fujii S, Sobel BE. Induction of plasminogen activator inhibitor type-1 (PAI-1) by proinsulin and insulin in vivo. Circulation. 1995;91:764-70.
78. Dai W, Zhang H, Lund H, et al. Intracellular tPA-PAI-1 interaction determines VLDL assembly in hepatocytes. Science. 2023;381:eadh5207.
79. Levine JA, Oleaga C, Eren M, et al. Role of PAI-1 in hepatic steatosis and dyslipidemia. Sci Rep. 2021;11:430.
80. Levine J, Sun T, Eren M, et al. OR22-6 reversal of diet induced metabolic syndrome in mice with an orally active small molecule inhibitor of PAI-1. J Endocr Soc. 2019;3:OR22-6.
81. Donato AJ, Machin DR, Lesniewski LA. Mechanisms of dysfunction in the aging vasculature and role in age-related disease. Circ Res. 2018;123:825-48.
82. Folsom AR, Qamhieh HT, Wing RR, et al. Impact of weight loss on plasminogen activator inhibitor (PAI-1), factor VII, and other hemostatic factors in moderately overweight adults. Arterioscler Thromb. 1993;13:162-9.
83. Bareja A, Lee DE, Ho T, et al. Liver-derived plasminogen mediates muscle stem cell expansion during caloric restriction through the plasminogen receptor Plg-R(KT). Cell Rep. 2024;43:113881.
84. Hong SH, Choi KM. Sarcopenic obesity, insulin resistance, and their implications in cardiovascular and metabolic consequences. Int J Mol Sci. 2020;21:494.
85. Silverthorn DU. Human physiology: an integrated approach. 2020. Available from: https://archive.org/details/humanphysiologyi0000silv_x2f9 [Last accessed on 22 Apr 2025].
86. Buchanan S, Combet E, Stenvinkel P, Shiels PG. Klotho, aging, and the failing kidney. Front Endocrinol. 2020;11:560.
87. Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390:45-51.
88. Hu MC, Shi M, Zhang J, et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol. 2011;22:124-36.
89. Eren M, Boe AE, Murphy SB, et al. PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice. Proc Natl Acad Sci USA. 2014;111:7090-5.
91. Gehlot P, Brünnert D, Kaushik V, et al. Unconventional localization of PAI-1 in PML bodies: a possible link with cellular growth of endothelial cells. Biochem Biophys Rep. 2024;39:101793.
92. Furuya H, Sasaki Y, Chen R, et al. PAI-1 is a potential transcriptional silencer that supports bladder cancer cell activity. Sci Rep. 2022;12:12186.
93. Zhang D, Zhang JW, Xu H, et al. Therapy-induced senescent tumor cell-derived extracellular vesicles promote colorectal cancer progression through SERPINE1-mediated NF-κB p65 nuclear translocation. Mol Cancer. 2024;23:70.
94. Fay WP, Parker AC, Condrey LR, Shapiro AD. Human plasminogen activator inhibitor-1 (PAI-1) deficiency: characterization of a large kindred with a null mutation in the PAI-1 gene. Blood. 1997;90:204-8.
