REFERENCES
1. American Heart Association. 2022 heart disease & stroke statistical update fact sheet global burden of disease. Available from: https://www.heart.org/-/media/PHD-Files-2/Science-News/2/2022-Heart-and-Stroke-Stat-Update/2022-Stat-Update-factsheet-GIobal-Burden-of-Disease.pdf [Last accessed on 20 Apr 2023].
2. Yazdanyar A, Newman AB. The burden of cardiovascular disease in the elderly: morbidity, mortality, and costs. Clin Geriatr Med 2009;25:563-77, vii.
3. World population prospects 2022 summary of results. Available from: https://www.un.org/development/desa/pd/sites/www.un.org.development.desa.pd/files/wpp2022_summary_of_results.pdf [Last accessed on 20 Apr 2023].
4. Levy D, Anderson KM, Savage DD, Kannel WB, Christiansen JC, Castelli WP. Echocardiographically detected left ventricular hypertrophy: prevalence and risk factors. The framingham heart study. Ann Intern Med 1988;108:7-13.
5. Schulman SP, Lakatta EG, Fleg JL, Lakatta L, Becker LC, Gerstenblith G. Age-related decline in left ventricular filling at rest and exercise. Am J Physiol 1992;263:H1932-8.
6. Debessa CR, Mesiano Maifrino LB, Rodrigues de Souza R. Age related changes of the collagen network of the human heart. Mech Ageing Dev 2001;122:1049-58.
7. Chen CH, Nakayama M, Nevo E, Fetics BJ, Maughan WL, Kass DA. Coupled systolic-ventricular and vascular stiffening with age: implications for pressure regulation and cardiac reserve in the elderly. J Am Coll Cardiol 1998;32:1221-7.
8. Egashira K, Inou T, Hirooka Y, et al. Effects of age on endothelium-dependent vasodilation of resistance coronary artery by acetylcholine in humans. Circulation 1993;88:77-81.
9. Judge S, Jang YM, Smith A, Hagen T, Leeuwenburgh C. Age-associated increases in oxidative stress and antioxidant enzyme activities in cardiac interfibrillar mitochondria: implications for the mitochondrial theory of aging. FASEB J 2005;19:419-21.
10. Chang E, Harley CB. Telomere length and replicative aging in human vascular tissues. Proc Natl Acad Sci USA 1995;92:11190-4.
11. Peng L, Zhuang X, Liao L, et al. Changes in cell autophagy and apoptosis during age-related left ventricular remodeling in mice and their potential mechanisms. Biochem Biophys Res Commun 2013;430:822-6.
13. Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol 2005;25:932-43.
14. Donato AJ, Eskurza I, Silver AE, et al. Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-kappaB. Circ Res 2007;100:1659-66.
15. O’Rourke MF, Hashimoto J. Mechanical factors in arterial aging: a clinical perspective. J Am Coll Cardiol 2007;50:1-13.
16. Messerli FH, Panjrath GS. The J-curve between blood pressure and coronary artery disease or essential hypertension: exactly how essential? J Am Coll Cardiol 2009;54:1827-34.
17. Cheng S, Xanthakis V, Sullivan LM, et al. Correlates of echocardiographic indices of cardiac remodeling over the adult life course: longitudinal observations from the Framingham Heart Study. Circulation 2010;122:570-8.
18. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation 2003;107:346-54.
19. Olivetti G, Melissari M, Capasso JM, Anversa P. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res 1991;68:1560-8.
20. Anversa P, Hiler B, Ricci R, Guideri G, Olivetti G. Myocyte cell loss and myocyte hypertrophy in the aging rat heart. J Am Coll Cardiol 1986;8:1441-8.
21. Sanders D, Dudley M, Groban L. Diastolic dysfunction, cardiovascular aging, and the anesthesiologist. Anesthesiol Clin 2009;27:497-517.
22. Lam CS, Rienstra M, Tay WT, et al. Atrial fibrillation in heart failure with preserved ejection fraction: association with exercise capacity, left ventricular filling pressures, natriuretic peptides, and left atrial volume. JACC Heart Fail 2017;5:92-8.
23. Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden of valvular heart diseases: a population-based study. Lancet 2006;368:1005-11.
24. Pomerance A. Ageing changes in human heart valves; 1967. Available from: http://heart.bmj.com [Last accessed on 20 Apr 2023].
25. Oomen PJA, Loerakker S, van Geemen D, et al. Age-dependent changes of stress and strain in the human heart valve and their relation with collagen remodeling. Acta Biomater 2016;29:161-9.
26. Kim KM, Valigorsky JM, Mergner WJ, Jones RT, Pendergrass RF, Trump BF. Aging changes in the human aortic valve in relation to dystrophic calcification. Hum Pathol 1976;7:47-60.
27. Rahman TT, Elabad AA, Elmenyawy KA, Mortagy AK. Risk factors of degenerative calcification of cardiac valves in the elderly. J Taibah Univ Med Sci 2006;1:42-7. Available from: https://core.ac.uk/download/pdf/82023734.pdf
28. Wang Y, Li Y, He C, Gou B, Song M. Mitochondrial regulation of cardiac aging. Biochim Biophys Acta Mol Basis Dis 2019;1865:1853-64.
29. HARMAN D. Aging: a theory based on free radical and radiation chemistry. J Gerontol 1956;11:298-300.
30. McMurray J, Chopra M, Abdullah I, Smith WE, Dargie HJ. Evidence of oxidative stress in chronic heart failure in humans. Eur Heart J 1993;14:1493-8.
31. Runge MS. The role of oxidative stress in atherosclerosis: the hope and the hype. Trans Am Clin Climatol Assoc 1999;110:119-29.
32. Touyz RM. Oxidative stress and vascular damage in hypertension. Curr Hypertens Rep 2000;2:98-105.
33. Samman Tahhan A, Sandesara PB, Hayek SS, et al. Association between oxidative stress and atrial fibrillation. Heart Rhythm 2017;14:1849-55.
35. Quan Y, Xin Y, Tian G, Zhou J, Liu X. Mitochondrial ROS-Modulated mtDNA: a potential target for cardiac aging. Oxid Med Cell Longev 2020;2020:9423593.
37. Chistiakov DA, Sobenin IA, Revin VV, Orekhov AN, Bobryshev YV. Mitochondrial aging and age-related dysfunction of mitochondria. Biomed Res Int 2014;2014:238463.
38. Dai DF, Santana LF, Vermulst M, et al. Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation 2009;119:2789-97.
39. Dai DF, Chen T, Wanagat J, et al. Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria. Aging Cell 2010;9:536-44.
40. Chiao YA, Zhang H, Sweetwyne M, et al. Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice. Elife 2020;9:1-26.
41. Ago T, Matsushima S, Kuroda J, Zablocki D, Kitazono T, Sadoshima J. The NADPH oxidase Nox4 and aging in the heart. Aging 2010;2:1012-6.
42. Vendrov AE, Vendrov KC, Smith A, et al. NOX4 NADPH oxidase-dependent mitochondrial oxidative stress in aging-associated cardiovascular disease. Antioxid Redox Signal 2015;23:1389-409.
43. Canugovi C, Stevenson MD, Vendrov AE, et al. Increased mitochondrial NADPH oxidase 4 (NOX4) expression in aging is a causative factor in aortic stiffening. Redox Biol 2019;26:101288.
44. Luo X, Yu W, Liu Z, et al. Ageing increases cardiac electrical remodelling in rats and mice via NOX4/ROS/CaMKII-Mediated calcium signalling. Oxid Med Cell Longev 2022;2022:8538296.
45. Nemoto S, Combs CA, French S, et al. The mammalian longevity-associated gene product p66shc regulates mitochondrial metabolism. J Biol Chem 2006;281:10555-60.
46. Giorgio M, Migliaccio E, Orsini F, et al. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 2005;122:221-33.
47. Ljubicic V, Menzies KJ, Hood DA. Mitochondrial dysfunction is associated with a pro-apoptotic cellular environment in senescent cardiac muscle. Mech Ageing Dev 2010;131:79-88.
48. Francia P, delli Gatti C, Bachschmid M, et al. Deletion of p66shc gene protects against age-related endothelial dysfunction. Circulation 2004;110:2889-95.
49. Mengozzi A, Costantino S, Paneni F, et al. Targeting SIRT1 rescues age- and obesity-induced microvascular dysfunction in ex vivo human vessels. Circ Res 2022;131:476-91.
50. Chen HZ, Wan YZ, Liu DP. Cross-talk between SIRT1 and p66Shc in vascular diseases. Trends Cardiovasc Med 2013;23:237-41.
51. Gano LB, Donato AJ, Pasha HM, Hearon CM Jr, Sindler AL, Seals DR. The SIRT1 activator SRT1720 reverses vascular endothelial dysfunction, excessive superoxide production, and inflammation with aging in mice. Am J Physiol Heart Circ Physiol 2014;307:H1754-63.
52. Xiong Y, Yu Y, Montani JP, Yang Z, Ming XF. Arginase-II induces vascular smooth muscle cell senescence and apoptosis through p66Shc and p53 independently of its l-arginine ureahydrolase activity: implications for atherosclerotic plaque vulnerability. J Am Heart Assoc 2013;2:e000096.
53. Yepuri G, Velagapudi S, Xiong Y, et al. Positive crosstalk between arginase-II and S6K1 in vascular endothelial inflammation and aging. Aging Cell 2012;11:1005-16.
54. Xiong Y, Yepuri G, Montani JP, Ming XF, Yang Z. Arginase-II deficiency extends lifespan in mice. Front Physiol 2017;8:682.
55. Ungvari Z, Bailey-Downs L, Gautam T, et al. Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-{kappa}B activation in the nonhuman primate Macaca mulatta. J Gerontol A Biol Sci Med Sci 2011;66:866-75.
56. Yang X, Jia J, Ding L, Yu Z, Qu C. The Role of Nrf2 in D-galactose-induced cardiac aging in mice: involvement of oxidative stress. Gerontology 2021;67:91-100.
57. Chen K, Wang S, Sun QW, Zhang B, Ullah M, Sun Z. Klotho deficiency causes heart aging via impairing the Nrf2-GR pathway. Circ Res 2021;128:492-507.
58. Pedersen L, Pedersen SM, Brasen CL, Rasmussen LM. Soluble serum Klotho levels in healthy subjects. Comparison of two different immunoassays. Clin Biochem 2013;46:1079-83.
59. Nakano M, Mizuno T, Katoh H, Gotoh S. Age-related accumulation of lipofuscin in myocardium of Japanese monkey (Macaca fuscata). Mech Ageing Dev 1989;49:41-8.
60. Taneike M, Yamaguchi O, Nakai A, et al. Inhibition of autophagy in the heart induces age-related cardiomyopathy. Autophagy 2010;6:600-6.
61. Weichhart T. mTOR as regulator of lifespan, aging, and cellular senescence: a mini-review. Gerontology 2018;64:127-34.
62. Loewith R, Jacinto E, Wullschleger S, et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 2002;10:457-68.
63. Hua Y, Zhang Y, Ceylan-Isik AF, Wold LE, Nunn JM, Ren J. Chronic akt activation accentuates aging-induced cardiac hypertrophy and myocardial contractile dysfunction: role of autophagy. Basic Res Cardiol 2011;106:1173-91.
64. Lesniewski LA, Seals DR, Walker AE, et al. Dietary rapamycin supplementation reverses age-related vascular dysfunction and oxidative stress, while modulating nutrient-sensing, cell cycle, and senescence pathways. Aging Cell 2017;16:17-26.
65. Zhou J, Freeman TA, Ahmad F, et al. GSK-3α is a central regulator of age-related pathologies in mice. J Clin Invest 2013;123:1821-32.
66. Shi J, Surma M, Yang Y, Wei L. Disruption of both ROCK1 and ROCK2 genes in cardiomyocytes promotes autophagy and reduces cardiac fibrosis during aging. FASEB J 2019;33:7348-62.
67. Li Y, Tai HC, Sladojevic N, Kim HH, Liao JK. Vascular stiffening mediated by Rho-associated coiled-coil containing kinase isoforms. J Am Heart Assoc 2021;10:e022568.
68. Balgi AD, Fonseca BD, Donohue E, et al. Screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mTORC1 signaling. PLoS One 2009;4:e7124.
69. Chang K, Kang P, Liu Y, et al. TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2. Autophagy 2020;16:1807-22.
70. Matsui Y, Takagi H, Qu X, et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res 2007;100:914-22.
71. Li Y, Chen C, Yao F, et al. AMPK inhibits cardiac hypertrophy by promoting autophagy via mTORC1. Arch Biochem Biophys 2014;558:79-86.
72. Turdi S, Fan X, Li J, et al. AMP-activated protein kinase deficiency exacerbates aging-induced myocardial contractile dysfunction. Aging Cell 2010;9:592-606.
73. Lesniewski LA, Zigler MC, Durrant JR, Donato AJ, Seals DR. Sustained activation of AMPK ameliorates age-associated vascular endothelial dysfunction via a nitric oxide-independent mechanism. Mech Ageing Dev 2012;133:368-71.
74. Wang L, Quan N, Sun W, et al. Cardiomyocyte-specific deletion of Sirt1 gene sensitizes myocardium to ischaemia and reperfusion injury. Cardiovasc Res 2018;114:805-21.
75. Wang S, Kandadi MR, Ren J. Double knockout of Akt2 and AMPK predisposes cardiac aging without affecting lifespan: role of autophagy and mitophagy. Biochim Biophys Acta Mol Basis Dis 2019;1865:1865-75.
76. Wu NN, Zhang Y, Ren J. Mitophagy, mitochondrial dynamics, and homeostasis in cardiovascular aging. Oxid Med Cell Longev 2019;2019:9825061.
77. Gao B, Yu W, Lv P, Liang X, Sun S, Zhang Y. Parkin overexpression alleviates cardiac aging through facilitating K63-polyubiquitination of TBK1 to facilitate mitophagy. Biochim Biophys Acta Mol Basis Dis 2021;1867:165997.
78. 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.
79. Rowe JW, Minaker KL, Pallotta JA, Flier JS. Characterization of the insulin resistance of aging. J Clin Invest 1983;71:1581-7.
80. Fink RI, Kolterman OG, Griffin J, Olefsky JM. Mechanisms of insulin resistance in aging. J Clin Invest 1983;71:1523-35.
81. Wang L, Ma W, Markovich R, Chen JW, Wang PH. Regulation of cardiomyocyte apoptotic signaling by insulin-like growth factor I. Circ Res 1998;83:516-22.
82. Ren J, Samson WK, Sowers JR. Insulin-like growth factor I as a cardiac hormone: physiological and pathophysiological implications in heart disease. J Mol Cell Cardiol 1999;31:2049-61.
83. Abdellatif M, Trummer-Herbst V, Heberle AM, et al. Fine-tuning cardiac insulin-like growth factor 1 receptor signaling to promote health and longevity. Circulation 2022;145:1853-66.
84. Moellendorf S, Kessels C, Peiseler L, et al. IGF-IR signaling attenuates the age-related decline of diastolic cardiac function. Am J Physiol Endocrinol Metab 2012;303:E213-22.
85. Inuzuka Y, Okuda J, Kawashima T, et al. Suppression of phosphoinositide 3-kinase prevents cardiac aging in mice. Circulation 2009;120:1695-703.
87. Babušíková E, Lehotský J, Dobrota D, Račay P, Kaplán P. Age-associated changes in Ca2+-ATPase and oxidative damage in sarcoplasmic reticulum of rat heart. Physiol Res 2012;61:453-60.
88. Qin F, Siwik DA, Lancel S, et al. Hydrogen peroxide-mediated SERCA cysteine 674 oxidation contributes to impaired cardiac myocyte relaxation in senescent mouse heart. J Am Heart Assoc 2013;2:e000184.
89. Upadhya B, Taffet GE, Cheng CP, Kitzman DW. Heart failure with preserved ejection fraction in the elderly: scope of the problem. J Mol Cell Cardiol 2015;83:73-87.
90. Yeh CH, Chou YJ, Kao CH, Tsai TF. Mitochondria and calcium homeostasis: Cisd2 as a big player in cardiac ageing. Int J Mol Sci 2020;21:9238.
91. Yeh CH, Shen ZQ, Hsiung SY, et al. Cisd2 is essential to delaying cardiac aging and to maintaining heart functions. PLoS Biol 2019;17:e3000508.
92. Hunter WG, Kelly JP, McGarrah RW 3rd, Kraus WE, Shah SH. Metabolic dysfunction in heart failure: diagnostic, prognostic, and pathophysiologic insights from metabolomic profiling. Curr Heart Fail Rep 2016;13:119-31.
93. Schmidt DR, Patel R, Kirsch DG, Lewis CA, Vander Heiden MG, Locasale JW. Metabolomics in cancer research and emerging applications in clinical oncology. CA Cancer J Clin 2021;71:333-58.
94. Wilkins JM, Trushina E. Application of metabolomics in alzheimer’s disease. Front Neurol 2017;8:719.
95. de Lucia C, Piedepalumbo M, Wang L, et al. Effects of myocardial ischemia/reperfusion injury on plasma metabolomic profile during aging. Aging Cell 2021;20:e13284.
96. Seo C, Hwang YH, Kim Y, et al. Metabolomic study of aging in mouse plasma by gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2016;1025:1-6.
97. Johnson LC, Parker K, Aguirre BF, et al. The plasma metabolome as a predictor of biological aging in humans. Geroscience 2019;41:895-906.
98. De Favari Signini É, Castro A, Rehder-Santos P, et al. Integrative perspective of the healthy aging process considering the metabolome, cardiac autonomic modulation and cardiorespiratory fitness evaluated in age groups. Sci Rep 2022;12:21314.
99. Pallister T, Jackson MA, Martin TC, et al. Hippurate as a metabolomic marker of gut microbiome diversity: Modulation by diet and relationship to metabolic syndrome. Sci Rep 2017;7:13670.
100. Ho KJ, Ramirez JL, Kulkarni R, et al. Plasma gut microbe-derived metabolites associated with peripheral artery disease and major adverse cardiac events. Microorganisms 2022;10:2065.
101. Franceschi C, Bonafè M, Valensin S, et al. Inflamm-aging. an evolutionary perspective on immunosenescence. Ann N Y Acad Sci 2000;908:244-54.
102. Liberale L, Montecucco F, Tardif JC, Libby P, Camici GG. Inflamm-ageing: the role of inflammation in age-dependent cardiovascular disease. Eur Heart J 2020;41:2974-82.
103. Puspitasari YM, Ministrini S, Schwarz L, Karch C, Liberale L, Camici GG. Modern concepts in cardiovascular disease: inflamm-aging. Front Cell Dev Biol 2022;10:882211.
104. Tong Y, Wang Z, Cai L, Lin L, Liu J, Cheng J. NLRP3 inflammasome and its central role in the cardiovascular diseases. Oxid Med Cell Longev 2020;2020:4293206.
105. Youm YH, Grant RW, McCabe LR, et al. Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab 2013;18:519-32.
106. Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 2019;19:477-89.
107. Liao LZ, Chen ZC, Wang SS, Liu WB, Zhao CL, Zhuang XD. NLRP3 inflammasome activation contributes to the pathogenesis of cardiocytes aging. Aging 2021;13:20534-51.
108. Yin Y, Zhou Z, Liu W, Chang Q, Sun G, Dai Y. Vascular endothelial cells senescence is associated with NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation via reactive oxygen species (ROS)/thioredoxin-interacting protein (TXNIP) pathway. Int J Biochem Cell Biol 2017;84:22-34.
109. Liu H, Chu S, Wu Z. Loss of toll-like receptor 4 ameliorates cardiovascular dysfunction in aged mice. Immun Ageing 2021;18:42.
110. Wang Y, Wang K, Bao Y, et al. The serum soluble Klotho alleviates cardiac aging and regulates M2a/M2c macrophage polarization via inhibiting TLR4/Myd88/NF-κB pathway. Tissue Cell 2022;76:101812.
111. Csiszar A, Smith K, Labinskyy N, Orosz Z, Rivera A, Ungvari Z. Resveratrol attenuates TNF-alpha-induced activation of coronary arterial endothelial cells: role of NF-kappaB inhibition. Am J Physiol Heart Circ Physiol 2006;291:H1694-9.
112. Csiszar A, Wang M, Lakatta EG, Ungvari Z. Inflammation and endothelial dysfunction during aging: role of NF-kappaB. J Appl Physiol 2008;105:1333-41.
113. Cong W, Niu C, Lv L, et al. Metallothionein prevents age-associated cardiomyopathy via inhibiting NF-κB pathway activation and associated nitrative damage to 2-OGD. Antioxid Redox Signal 2016;25:936-52.
114. Wang X, Li X, Ong H, et al. MG53 suppresses NF-κB activation to mitigate age-related heart failure. JCI Insight 2021;6:e148375.
115. Chiao YA, Dai Q, Zhang J, et al. Multi-analyte profiling reveals matrix metalloproteinase-9 and monocyte chemotactic protein-1 as plasma biomarkers of cardiac aging. Circ Cardiovasc Genet 2011;4:455-62.
116. Ma Y, Chiao YA, Clark R, et al. Deriving a cardiac ageing signature to reveal MMP-9-dependent inflammatory signalling in senescence. Cardiovasc Res 2015;106:421-31.
117. Horn MA, Trafford AW. Aging and the cardiac collagen matrix: novel mediators of fibrotic remodelling. J Mol Cell Cardiol 2016;93:175-85.
118. Kajstura J, Cheng W, Sarangarajan R, et al. Necrotic and apoptotic myocyte cell death in the aging heart of Fischer 344 rats. Am J Physiol 1996;271:H1215-28.
119. Porter KE, Turner NA. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther 2009;123:255-78.
120. Camelliti P, Borg TK, Kohl P. Structural and functional characterisation of cardiac fibroblasts. Cardiovasc Res 2005;65:40-51.
121. Meyer K, Hodwin B, Ramanujam D, Engelhardt S, Sarikas A. Essential role for premature senescence of myofibroblasts in myocardial fibrosis. J Am Coll Cardiol 2016;67:2018-28.
122. Brooks WW, Conrad CH. Myocardial fibrosis in transforming growth factor β1 heterozygous mice. J Mol Cell Cardiol 2000;32:187-95.
123. Derangeon M, Montnach J, Cerpa CO, et al. Transforming growth factor β receptor inhibition prevents ventricular fibrosis in a mouse model of progressive cardiac conduction disease. Cardiovasc Res 2017;113:464-74.
124. Cieslik KA, Trial J, Crawford JR, Taffet GE, Entman ML. Adverse fibrosis in the aging heart depends on signaling between myeloid and mesenchymal cells; role of inflammatory fibroblasts. J Mol Cell Cardiol 2014;70:56-63.
125. Frangogiannis NG. Transforming growth factor-β in myocardial disease. Nat Rev Cardiol 2022;19:435-55.
126. Wang M, Zhang J, Walker SJ, Dworakowski R, Lakatta EG, Shah AM. Involvement of NADPH oxidase in age-associated cardiac remodeling. J Mol Cell Cardiol 2010;48:765-72.
127. Yoon HE, Kim EN, Kim MY, et al. Age-Associated changes in the vascular renin-angiotensin system in mice. Oxid Med Cell Longev 2016;2016:6731093.
128. Kim SK, McCurley AT, DuPont JJ, et al. Smooth muscle cell-mineralocorticoid receptor as a mediator of cardiovascular stiffness with aging. Hypertension 2018;71:609-21.
129. Friebel J, Weithauser A, Witkowski M, et al. Protease-activated receptor 2 deficiency mediates cardiac fibrosis and diastolic dysfunction. Eur Heart J 2019;40:3318-32.
130. Maruyama K, Kagota S, McGuire JJ, et al. Age-related changes to vascular protease-activated receptor 2 in metabolic syndrome: a relationship between oxidative stress, receptor expression, and endothelium-dependent vasodilation. Can J Physiol Pharmacol 2017;95:356-64.
132. d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 2003;426:194-8.
133. Rossiello F, Jurk D, Passos JF, d’Adda di Fagagna F. Telomere dysfunction in ageing and age-related diseases. Nat Cell Biol 2022;24:135-47.
134. Zhan Y, Hägg S. Telomere length and cardiovascular disease risk. Curr Opin Cardiol 2019;34:270-4.
135. Sahin E, Colla S, Liesa M, et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 2011;470:359-65.
136. Moslehi J, DePinho RA, Sahin E. Telomeres and mitochondria in the aging heart. Circ Res 2012;110:1226-37.
137. Leri A, Franco S, Zacheo A, et al. Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation. EMBO J 2003;22:131-9.
138. Bhayadia R, Schmidt BM, Melk A, Hömme M. Senescence-Induced oxidative stress causes endothelial dysfunction. J Gerontol A Biol Sci Med Sci 2016;71:161-9.
139. Cai Y, Liu H, Song E, et al. Deficiency of telomere-associated repressor activator protein 1 precipitates cardiac aging in mice via p53/PPARα signaling. Theranostics 2021;11:4710-27.
140. Shay JW, Wright WE. Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis 2005;26:867-74.
142. Yan M, Sun S, Xu K, et al. Cardiac aging: from basic research to therapeutics. Oxid Med Cell Longev 2021;2021:9570325.
143. Anderson R, Lagnado A, Maggiorani D, et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J 2019:38.
144. Cieslik KA, Taffet GE, Carlson S, Hermosillo J, Trial J, Entman ML. Immune-inflammatory dysregulation modulates the incidence of progressive fibrosis and diastolic stiffness in the aging heart. J Mol Cell Cardiol 2011;50:248-56.
145. Zhang TY, Zhao BJ, Wang T, Wang J. Effect of aging and sex on cardiovascular structure and function in wildtype mice assessed with echocardiography. Sci Rep 2021;11:22800.
146. Roth GS, Mattison JA, Ottinger MA, Chachich ME, Lane MA, Ingram DK. Aging in rhesus monkeys: relevance to human health interventions. Science 2004;305:1423-6.
147. Takeda T, Hosokawa M, Higuchi K, Hosono M, Akiguchi I, Katoh H. A novel murine model of aging, Senescence-Accelerated Mouse (SAM). Arch Gerontol Geriatr 1994;19:185-92.
148. Reed AL, Tanaka A, Sorescu D, et al. Diastolic dysfunction is associated with cardiac fibrosis in the senescence-accelerated mouse. Am J Physiol Heart Circ Physiol 2011;301:H824-31.
149. Matsumoto C, Jiang Y, Emathinger J, et al. Short telomeres induce p53 and autophagy and modulate age-associated changes in cardiac progenitor cell fate. Stem Cells 2018;36:868-80.
150. Wang SS, Zhang X, Ke ZZ, et al. D-galactose-induced cardiac ageing: A review of model establishment and potential interventions. J Cell Mol Med 2022;26:5335-59.
151. Bo-Htay C, Shwe T, Higgins L, et al. Aging induced by D-galactose aggravates cardiac dysfunction via exacerbating mitochondrial dysfunction in obese insulin-resistant rats. Geroscience 2020;42:233-49.
152. Bo-Htay C, Shwe T, Jaiwongkam T, et al. Hyperbaric oxygen therapy effectively alleviates D-galactose-induced-age-related cardiac dysfunction via attenuating mitochondrial dysfunction in pre-diabetic rats. Aging 2021;13:10955-72.
153. Yang L, Shi J, Wang X, Zhang R. Curcumin alleviates D-galactose-induced cardiomyocyte senescence by promoting autophagy via the SIRT1/AMPK/mTOR pathway. Evid Based Complement Alternat Med 2022;2022:2990843.
154. Lin HJ, Ramesh S, Chang YM, et al. D-galactose-induced toxicity associated senescence mitigated by alpinate oxyphyllae fructus fortified adipose-derived mesenchymal stem cells. Environ Toxicol ;2020:86-94.
155. Brayson D, Shanahan CM. Current insights into LMNA cardiomyopathies: existing models and missing LINCs. Nucleus 2017;8:17-33.
156. Zaghini A, Sarli G, Barboni C, et al. Long term breeding of the Lmna G609G progeric mouse: characterization of homozygous and heterozygous models. Exp Gerontol 2020;130:110784.
157. Fanjul V, Jorge I, Camafeita E, et al. Identification of common cardiometabolic alterations and deregulated pathways in mouse and pig models of aging. Aging Cell 2020;19:e13203.
158. Woodall BP, Orogo AM, Najor RH, et al. Parkin does not prevent accelerated cardiac aging in mitochondrial DNA mutator mice. JCI Insight 2019;5:127713.
159. Li H, Hastings MH, Rhee J, Trager LE, Roh JD, Rosenzweig A. Targeting age-related pathways in heart failure. Circ Res 2020;126:533-51.
160. Koczor CA, Ludlow I, Fields E, et al. Mitochondrial polymerase gamma dysfunction and aging cause cardiac nuclear DNA methylation changes. Physiol Genomics 2016;48:274-80.
161. Golob MJ, Tian L, Wang Z, et al. Mitochondria DNA mutations cause sex-dependent development of hypertension and alterations in cardiovascular function. J Biomech 2015;48:405-12.
162. Levy WC, Cerqueira MD, Abrass IB, Schwartz RS, Stratton JR. Endurance exercise training augments diastolic filling at rest and during exercise in healthy young and older men. Circulation 1993;88:116-26.
163. Seals DR, Hagberg JM, Spina RJ, Rogers MA, Schechtman KB, Ehsani AA. Enhanced left ventricular performance in endurance trained older men. Circulation 1994;89:198-205.
165. Clayton ZS, Craighead DH, Darvish S, et al. Promoting healthy cardiovascular aging: emerging topics. J Cardiovasc Aging 2022;2:43.
166. Fujimoto N, Prasad A, Hastings JL, et al. Cardiovascular effects of 1 year of progressive and vigorous exercise training in previously sedentary individuals older than 65 years of age. Circulation 2010;122:1797-805.
167. Roh JD, Houstis N, Yu A, et al. Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice. Aging Cell 2020;19:e13159.
168. Lerchenmüller C, Vujic A, Mittag S, et al. Restoration of cardiomyogenesis in aged mouse hearts by voluntary exercise. Circulation 2022;146:412-26.
169. Elhelaly W, Sadek H. Exercise induces cardiomyogenesis in the aged heart. J Cardiovasc Aging 2023;3:18.
170. Safdar A, Bourgeois JM, Ogborn DI, et al. Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. Proc Natl Acad Sci USA 2011;108:4135-40.
171. Yeo HS, Lim JY. Effects of different types of exercise training on angiogenic responses in the left ventricular muscle of aged rats. Exp Gerontol 2022;158:111650.
172. Wu T, Li H, Wu B, et al. Hydrogen sulfide reduces recruitment of CD11b+Gr-1+ cells in mice with myocardial infarction. Cell Transplant 2017;26:753-64.
173. Snijder PM, Frenay AR, de Boer RA, et al. Exogenous administration of thiosulfate, a donor of hydrogen sulfide, attenuates angiotensin II-induced hypertensive heart disease in rats. Br J Pharmacol 2015;172:1494-504.
174. Meng G, Zhu J, Xiao Y, et al. Hydrogen sulfide donor GYY4137 protects against myocardial fibrosis. Oxid Med Cell Longev 2015;2015:691070.
175. Ma N, Liu HM, Xia T, Liu JD, Wang XZ. Chronic aerobic exercise training alleviates myocardial fibrosis in aged rats through restoring bioavailability of hydrogen sulfide. Can J Physiol Pharmacol 2018;96:902-8.
177. Sheng Y, Lv S, Huang M, et al. Opposing effects on cardiac function by calorie restriction in different-aged mice. Aging Cell 2017;16:1155-67.
178. Shinmura K, Tamaki K, Sano M, et al. Impact of long-term caloric restriction on cardiac senescence: caloric restriction ameliorates cardiac diastolic dysfunction associated with aging. J Mol Cell Cardiol 2011;50:117-27.
179. Granado M, Amor S, Martín-Carro B, et al. Caloric restriction attenuates aging-induced cardiac insulin resistance in male Wistar rats through activation of PI3K/Akt pathway. Nutr Metab Cardiovasc Dis 2019;29:97-105.
180. Donato AJ, Walker AE, Magerko KA, et al. Life-long caloric restriction reduces oxidative stress and preserves nitric oxide bioavailability and function in arteries of old mice. Aging Cell 2013;12:772-83.
181. Madeo F, Carmona-Gutierrez D, Hofer SJ, Kroemer G. Caloric restriction mimetics against age-associated disease: targets, mechanisms, and therapeutic potential. Cell Metab 2019;29:592-610.
182. Pang L, Jiang X, Lian X, et al. Caloric restriction-mimetics for the reduction of heart failure risk in aging heart: with consideration of gender-related differences. Mil Med Res 2022;9:33.
183. Börzsei D, Sebestyén J, Szabó R, et al. Resveratrol as a promising polyphenol in age-associated cardiac alterations. Oxid Med Cell Longev 2022;2022:7911222.
184. Torregrosa-Muñumer R, Vara E, Fernández-Tresguerres JÁ, Gredilla R. Resveratrol supplementation at old age reverts changes associated with aging in inflammatory, oxidative and apoptotic markers in rat heart. Eur J Nutr 2021;60:2683-93.
185. Sin TK, Tam BT, Yung BY, et al. Resveratrol protects against doxorubicin-induced cardiotoxicity in aged hearts through the SIRT1-USP7 axis. J Physiol 2015;593:1887-99.
186. Zhang L, Chen J, Yan L, He Q, Xie H, Chen M. Resveratrol ameliorates cardiac remodeling in a murine model of heart failure with preserved ejection fraction. Front Pharmacol 2021;12:646240.
187. Fleenor BS, Sindler AL, Marvi NK, et al. Curcumin ameliorates arterial dysfunction and oxidative stress with aging. Exp Gerontol 2013;48:269-76.
188. Santos-Parker JR, Strahler TR, Bassett CJ, Bispham NZ, Chonchol MB, Seals DR. Curcumin supplementation improves vascular endothelial function in healthy middle-aged and older adults by increasing nitric oxide bioavailability and reducing oxidative stress. Aging 2017;9:187-208.
189. LaRocca TJ, Gioscia-Ryan RA, Hearon CM Jr, Seals DR. The autophagy enhancer spermidine reverses arterial aging. Mech Ageing Dev 2013;134:314-20.
190. Eisenberg T, Abdellatif M, Schroeder S, et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med 2016;22:1428-38.
191. Zhang H, Wang J, Li L, et al. Spermine and spermidine reversed age-related cardiac deterioration in rats. Oncotarget 2017;8:64793-808.
192. Wang J, Li S, Wang J, et al. Spermidine alleviates cardiac aging by improving mitochondrial biogenesis and function. Aging 2020;12:650-71.
193. Bose C, Alves I, Singh P, et al. Sulforaphane prevents age-associated cardiac and muscular dysfunction through Nrf2 signaling. Aging Cell 2020;19:e13261.
194. Mehdizadeh M, Aguilar M, Thorin E, Ferbeyre G, Nattel S. The role of cellular senescence in cardiac disease: basic biology and clinical relevance. Nat Rev Cardiol 2022;19:250-64.
195. Salerno N, Marino F, Scalise M, et al. Pharmacological clearance of senescent cells improves cardiac remodeling and function after myocardial infarction in female aged mice. Mech Ageing Dev 2022;208:111740.
196. Roos CM, Zhang B, Palmer AK, et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 2016;15:973-7.
197. 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.
198. Flynn JM, O’Leary MN, Zambataro CA, et al. Late-life rapamycin treatment reverses age-related heart dysfunction. Aging Cell 2013;12:851-62.
199. Urfer SR, Kaeberlein TL, Mailheau S, et al. A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. Geroscience 2017;39:117-27.
200. Quarles E, Basisty N, Chiao YA, et al. Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment. Aging Cell 2020;19:e13086.
201. Ramos FJ, Chen SC, Garelick MG, et al. Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival. Sci Transl Med 2012;4:144ra103.
202. Zhang ZD, Milman S, Lin JR, et al. Genetics of extreme human longevity to guide drug discovery for healthy ageing. Nat Metab 2020;2:663-72.
203. Justice JN, Niedernhofer L, Robbins PD, et al. Development of clinical trials to extend healthy lifespan. Cardiovasc Endocrinol Metab 2018;7:80-3.
204. Kulkarni AS, Brutsaert EF, Anghel V, et al. Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults. Aging Cell 2018;17:e12723.
205. Tai S, Sun J, Zhou Y, et al. Metformin suppresses vascular smooth muscle cell senescence by promoting autophagic flux. J Adv Res 2022;41:205-18.
206. Chen Q, Thompson J, Hu Y, Lesnefsky EJ. Chronic metformin treatment decreases cardiac injury during ischemia-reperfusion by attenuating endoplasmic reticulum stress with improved mitochondrial function. Aging 2021;13:7828-45.
207. Zhu X, Shen W, Liu Z, et al. Effect of metformin on cardiac metabolism and longevity in aged female mice. Front Cell Dev Biol 2020;8:626011.
208. La Grotta R, de Candia P, Olivieri F, et al. Anti-inflammatory effect of SGLT-2 inhibitors via uric acid and insulin. Cell Mol Life Sci 2022;79:273.
209. Evans M, Morgan AR, Davies S, Beba H, Strain WD. The role of sodium-glucose co-transporter-2 inhibitors in frail older adults with or without type 2 diabetes mellitus. Age Ageing 2022;51:1-8.
210. Soares RN, Ramirez-Perez FI, Cabral-Amador FJ, et al. SGLT2 inhibition attenuates arterial dysfunction and decreases vascular F-actin content and expression of proteins associated with oxidative stress in aged mice. Geroscience 2022;44:1657-75.
211. Madonna R, Doria V, Minnucci I, Pucci A, Pierdomenico DS, De Caterina R. Empagliflozin reduces the senescence of cardiac stromal cells and improves cardiac function in a murine model of diabetes. J Cell Mol Med 2020;24:12331-40.
212. Shiraki A, Oyama JI, Shimizu T, Nakajima T, Yokota T, Node K. Empagliflozin improves cardiac mitochondrial function and survival through energy regulation in a murine model of heart failure. Eur J Pharmacol 2022;931:175194.
213. Withaar C, Meems LMG, Markousis-Mavrogenis G, et al. The effects of liraglutide and dapagliflozin on cardiac function and structure in a multi-hit mouse model of heart failure with preserved ejection fraction. Cardiovasc Res 2021;117:2108-24.
214. Olgar Y, Tuncay E, Degirmenci S, et al. Ageing-associated increase in SGLT2 disrupts mitochondrial/sarcoplasmic reticulum Ca2+ homeostasis and promotes cardiac dysfunction. J Cell Mol Med 2020;24:8567-78.
215. Anker SD, Butler J, Filippatos G, et al. EMPEROR-Preserved trial investigators. empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021;385:1451-61.
216. Solomon SD, McMurray JJV, Claggett B, et al. DELIVER trial committees and investigators. dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med 2022;387:1089-98.
217. Kane AE, Bisset ES, Heinze-Milne S, Keller KM, Grandy SA, Howlett SE. Maladaptive Changes associated with cardiac aging are sex-specific and graded by frailty and inflammation in C57BL/6 mice. J Gerontol A Biol Sci Med Sci 2021;76:233-43.
218. De Moudt S, Hendrickx JO, Neutel C, et al. Progressive aortic stiffness in aging C57Bl/6 mice displays altered contractile behaviour and extracellular matrix changes. Commun Biol 2022;5:605.
219. Forman DE, Cittadini A, Azhar G, Douglas PS, Wei JY. Cardiac morphology and function in senescent rats: gender-related differences. J Am Coll Cardiol 1997;30:1872-7.
220. Chou C, Chin MT. Modeling heart failure with preserved ejection fraction in rodents: where do we stand? Front Drug Discov 2022;2:948407.
221. Walker EM, Nillas MS, Mangiarua EI, et al. Age-associated changes in hearts of male Fischer 344/Brown Norway F1 rats. Ann Clin Lab Sci 2006;36:427-38.
222. Karuppagounder V, Arumugam S, Babu SS, et al. The senescence accelerated mouse prone 8 (SAMP8): a novel murine model for cardiac aging. Ageing Res Rev 2017;35:291-6.
223. Mounkes LC, Kozlov SV, Rottman JN, Stewart CL. Expression of an LMNA-N195K variant of A-type lamins results in cardiac conduction defects and death in mice. Hum Mol Genet 2005;14:2167-80.
224. Arimura T, Helbling-Leclerc A, Massart C, et al. Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies. Hum Mol Genet 2005;14:155-69.
225. Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 2011;479:232-6.
226. Matsumoto T, Baker DJ, d’Uscio LV, Mozammel G, Katusic ZS, van Deursen JM. Aging-associated vascular phenotype in mutant mice with low levels of BubR1. Stroke 2007;38:1050-6.
227. Lewis W, Day BJ, Kohler JJ, et al. Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase gamma. Lab Invest 2007;87:326-35.
228. Gorr MW, Francois A, Marcho LM, et al. Molecular signature of cardiac remodeling associated with Polymerase Gamma mutation. Life Sci 2022;298:120469.
229. Acehan D, Vaz F, Houtkooper RH, et al. Cardiac and skeletal muscle defects in a mouse model of human Barth syndrome. J Biol Chem 2011;286:899-908.
230. Nojiri H, Shimizu T, Funakoshi M, et al. Oxidative stress causes heart failure with impaired mitochondrial respiration. J Biol Chem 2006;281:33789-801.
231. Blasco MA, Lee HW, Hande MP, et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 1997;91:25-34.
232. Wong LS, Oeseburg H, de Boer RA, van Gilst WH, van Veldhuisen DJ, van der Harst P. Telomere biology in cardiovascular disease: the TERC-/- mouse as a model for heart failure and ageing. Cardiovasc Res 2009;81:244-52.
233. Din S, Konstandin MH, Johnson B, et al. Metabolic dysfunction consistent with premature aging results from deletion of Pim kinases. Circ Res 2014;115:376-87.
234. Sikka G, Miller KL, Steppan J, et al. Interleukin 10 knockout frail mice develop cardiac and vascular dysfunction with increased age. Exp Gerontol 2013;48:128-35.
