CoChat
Sign Up
Cited by 304

The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.

The role of cellular senescence in cardiac disease: basic biology and clinical relevance

Mehdizadeh, Mozhdeh, Aguilar, Martin, Thorin, Eric, Ferbeyre, Gerardo, Nattel, Stanley·2022·Nature Reviews Cardiology
DOI 10.1038/s41569-021-00624-2
Open this paper in CoChat — free account

Abstract

Cellular senescence, classically defined as stable cell cycle arrest, is implicated in biological processes such as embryogenesis, wound healing and ageing. Senescent cells have a complex senescence-associated secretory phenotype (SASP), involving a range of pro-inflammatory factors with important paracrine and autocrine effects on cell and tissue biology. Clinical evidence and experimental studies link cellular senescence, senescent cell accumulation, and the production and release of SASP components with age-related cardiac pathologies such as heart failure, myocardial ischaemia and infarction, and cancer chemotherapy-related cardiotoxicity. However, the precise role of senescent cells in these conditions is unclear and, in some instances, both detrimental and beneficial effects have been reported. The involvement of cellular senescence in other important entities, such as cardiac arrhythmias and remodelling, is poorly understood. In this Review, we summarize the basic biology of cellular senescence and discuss what is known about the role of cellular senescence and the SASP in heart disease. We then consider the various approaches that are being developed to prevent the accumulation of senescent cells and their consequences. Many of these strategies are applicable in vivo and some are being investigated for non-cardiac indications in clinical trials. We end by considering important knowledge gaps, directions for future research and the potential implications for improving…

Overview

Integrity signals

Registry

Crossref · 10.1038/s41569-021-00624-2

Cites

49 of 49 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Verification

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Citations

Cites

Research works printed but not linked: 158

  1. Kuilman, T., Michaloglou, C., Mooi, W. J. & Peeper, D. S. The essence of senescence. Genes Dev. 24, 2463–2479 (2010). · DOI · Paper page
  2. Khosla, S., Farr, J. N., Tchkonia, T. & Kirkland, J. L. The role of cellular senescence in ageing and endocrine disease. Nat. Rev. Endocrinol. 16, 263–275 (2020). · DOI · Paper page
  3. Frey, N., Venturelli, S., Zender, L. & Bitzer, M. Cellular senescence in gastrointestinal diseases: from pathogenesis to therapeutics. Nat. Rev. Gastroenterol. Hepatol. 15, 81–95 (2018). · DOI · Paper page
  4. Sturmlechner, I., Durik, M., Sieben, C. J., Baker, D. J. & van Deursen, J. M. Cellular senescence in renal ageing and disease. Nat. Rev. Nephrol. 13, 77–89 (2017). · DOI · Paper page
  5. Shimizu, I. & Minamino, T. Cellular senescence in cardiac diseases. J. Cardiol. 74, 313–319 (2019). · DOI
  6. Storer, M. et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119–1130 (2013). · DOI · Paper page
  7. Paez-Ribes, M., Gonzalez-Gualda, E., Doherty, G. J. & Munoz-Espin, D. Targeting senescent cells in translational medicine. EMBO Mol. Med. 11, e10234 (2019). · DOI · Paper page
  8. Farr, J. N. et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23, 1072–1079 (2017). · DOI · Paper page
  9. Roos, C. M. et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 15, 973–977 (2016). · DOI · Paper page
  10. Xu, E. & Wen, H. X. Risk factors of cerebrovascular diseases and their intervention and management. Chin. J. Contemp. Neurol. Neurosurg. 15, 20–26 (2015).
  11. Spallarossa, P. 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. 297, H2169–H2181 (2009). · DOI
  12. Januzzi, J. L. et al. IGFBP7 (insulin-like growth factor-binding protein-7) and neprilysin inhibition in patients with heart failure. Circ. Heart Fail. 11, e005133 (2018). · DOI
  13. O’Rourke, M. F., Safar, M. E. & Dzau, V. The cardiovascular continuum extended: aging effects on the aorta and microvasculature. Vasc. Med. 15, 461–468 (2010). · DOI
  14. Hacker, T. A., McKiernan, S. H., Douglas, P. S., Wanagat, J. & Aiken, J. M. Age-related changes in cardiac structure and function in Fischer 344 x Brown Norway hybrid rats. Am. J. Physiol. Heart Circ. Physiol. 290, H304–H311 (2006). · DOI
  15. Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961). · DOI · Paper page
  16. Chang, E. & Harley, C. B. Telomere length and replicative aging in human vascular tissues. Proc. Natl Acad. Sci. USA 92, 11190–11194 (1995). · DOI
  17. Voghel, G. et al. Cellular senescence in endothelial cells from atherosclerotic patients is accelerated by oxidative stress associated with cardiovascular risk factors. Mech. Ageing Dev. 128, 662–671 (2007). · DOI
  18. Razgonova, M. P. et al. Telomerase and telomeres in aging theory and chronographic aging theory (Review). Mol. Med. Rep. 22, 1679–1694 (2020). · DOI · Paper page
  19. Mallette, F. A. & Ferbeyre, G. The DNA damage signaling pathway connects oncogenic stress to cellular senescence. Cell Cycle 6, 1831–1836 (2007). · DOI · Paper page
  20. Borghesan, M., Hoogaars, W. M. H., Varela-Eirin, M., Talma, N. & Demaria, M. A senescence-centric view of aging: implications for longevity and disease. Trends Cell Biol. 30, 777–791 (2020). · DOI · Paper page
  21. Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016). · DOI · Paper page
  22. Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016). · DOI · Paper page
  23. Feng, T. et al. CCN1-induced cellular senescence promotes heart regeneration. Circulation 139, 2495–2498 (2019). · DOI
  24. Grosse, L. et al. Defined p16(High) senescent cell types are indispensable for mouse healthspan. Cell Metab. 32, 87–99.e6 (2020). · DOI · Paper page
  25. Bueno, M. et al. Mitochondria, aging, and cellular senescence: implications for scleroderma. Curr. Rheumatol. Rep. 22, 37 (2020). · DOI
  26. Nacarelli, T., Azar, A. & Sell, C. Mitochondrial stress induces cellular senescence in an mTORC1-dependent manner. Free Radic. Biol. Med. 95, 133–154 (2016). · DOI
  27. Chapman, J., Fielder, E. & Passos, J. F. Mitochondrial dysfunction and cell senescence: deciphering a complex relationship. FEBS Lett. 593, 1566–1579 (2019). · DOI · Paper page
  28. Du, W. W. et al. The microRNA miR-17-3p inhibits mouse cardiac fibroblast senescence by targeting Par4. J. Cell Sci. 128, 293–304 (2015).
  29. Ito, T., Yagi, S. & Yamakuchi, M. MicroRNA-34a regulation of endothelial senescence. Biochem. Biophys. Res. Commun. 398, 735–740 (2010). · DOI
  30. Jazbutyte, V. et al. MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart. Age 35, 747–762 (2013). · DOI
  31. Bilsland, A. E., Revie, J. & Keith, W. MicroRNA and senescence: the senectome, integration and distributed control. Crit. Rev. Oncog. 18, 373–390 (2013). · DOI
  32. Ahn, J. S. et al. Aging-associated increase of gelsolin for apoptosis resistance. Biochem. Biophys. Res. Commun. 312, 1335–1341 (2003). · DOI
  33. Sokolova, M. et al. Palmitate promotes inflammatory responses and cellular senescence in cardiac fibroblasts. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1862, 234–245 (2017). · DOI
  34. Matsushita, H. et al. eNOS activity is reduced in senescent human endothelial cells: preservation by hTERT immortalization. Circ. Res. 89, 793–798 (2001). · DOI
  35. Bochenek, M. L., Schütz, E. & Schäfer, K. Endothelial cell senescence and thrombosis: ageing clots. Thromb. Res. 147, 36–45 (2016). · DOI · Paper page
  36. Tang, X., Li, P. H. & Chen, H. Z. Cardiomyocyte senescence and cellular communications within myocardial microenvironments. Front. Endocrinol. 11, 280 (2020). · DOI
  37. Li, H. et al. Targeting age-related pathways in heart failure. Circ. Res. 126, 533–551 (2020). · DOI
  38. Sun, T., Ghosh, A. K., Eren, M., Miyata, T. & Vaughan, D. E. PAI-1 contributes to homocysteine-induced cellular senescence. Cell. Signal. 64, 109394 (2019). · DOI
  39. Franceschi, C. et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. NY Acad. Sci. 908, 244–254 (2000). · DOI · Paper page
  40. Liberale, L., Montecucco, F., Tardif, J. C., Libby, P. & Camici, G. G. Inflamm-ageing: the role of inflammation in age-dependent cardiovascular disease. Eur. Heart J. 41, 2974–2982 (2020). · DOI
  41. Straub, R. H. & Schradin, C. Chronic inflammatory systemic diseases: an evolutionary trade-off between acutely beneficial but chronically harmful programs. Evol. Med. Public Health 2016, 37–51 (2016).
  42. He, S. & Sharpless, N. E. Senescence in health and disease. Cell 169, 1000–1011 (2017). · DOI · Paper page
  43. Palmer, A. K. et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell 18, e12950 (2019). · DOI · Paper page
  44. Ellison-Hughes, G. M. Senescent cells: targeting and therapeutic potential of senolytics in age-related diseases with a particular focus on the heart. Expert Opin. Ther. Targets 24, 819–823 (2020). · DOI
  45. Cianflone, E. et al. Targeting cardiac stem cell senescence to treat cardiac aging and disease. Cells 9, 1558 (2020). · DOI
  46. Moiseeva, O., Deschênes-Simard, X., Pollak, M. & Ferbeyre, G. Metformin, aging and cancer. Aging 5, 330–331 (2013). · DOI
  47. Park, J. H. et al. Pharmacological inhibition of mTOR attenuates replicative cell senescence and improves cellular function via regulating the STAT3-PIM1 axis in human cardiac progenitor cells. Exp. Mol. Med. 52, 615–628 (2020). · DOI
  48. Macip, S. et al. Inhibition of p21-mediated ROS accumulation can rescue p21-induced senescence. EMBO J. 21, 2180–2188 (2002). · DOI · Paper page
  49. Kosugi, R. et al. Angiotensin II receptor antagonist attenuates expression of aging markers in diabetic mouse heart. Circ. J. 70, 482–488 (2006). · DOI
  50. Katsuumi, G. et al. Catecholamine-induced senescence of endothelial cells and bone marrow cells promotes cardiac dysfunction in mice. Int. Heart J. 59, 837–844 (2018). · DOI
  51. Li, J. et al. Long-term repopulation of aged bone marrow stem cells using young Sca-1 cells promotes aged heart rejuvenation. Aging Cell 18, e13026 (2019). · DOI
  52. Cui, S. et al. Postinfarction hearts are protected by premature senescent cardiomyocytes via GATA4-dependent CCN1 secretion. J. Am. Heart Assoc. 7, e009111 (2018). · DOI
  53. Alam, P. et al. Inhibition of senescence-associated genes Rb1 and Meis2 in adult cardiomyocytes results in cell cycle reentry and cardiac repair post-myocardial infarction. J. Am. Heart Assoc. 8, e012089 (2019). · DOI
  54. Manzella, N. et al. Monoamine oxidase-A is a novel driver of stress-induced premature senescence through inhibition of parkin-mediated mitophagy. Aging Cell 17, e12811 (2018). · DOI
  55. Lorda-Diez, C. I. et al. Cell senescence, apoptosis and DNA damage cooperate in the remodeling processes accounting for heart morphogenesis. J. Anat. 234, 815–829 (2019). · DOI
  56. Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017). · DOI · Paper page
  57. Cheng, H. L. et al. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc. Natl Acad. Sci. USA 100, 10794–10799 (2003). · DOI · Paper page
  58. Wu, Y. et al. Pax8 plays a pivotal role in regulation of cardiomyocyte growth and senescence. J. Cell. Mol. Med. 20, 644–654 (2016). · DOI
  59. Laredo, M., Waldmann, V., Khairy, P. & Nattel, S. Age as a critical determinant of atrial fibrillation: a two-sided relationship. Can. J. Cardiol. 34, 1396–1406 (2018). · DOI
  60. Kuo, C. L., Pilling, L. C., Kuchel, G. A., Ferrucci, L. & Melzer, D. Telomere length and aging-related outcomes in humans: a Mendelian randomization study in 261,000 older participants. Aging Cell 18, e13017 (2019). · DOI
  61. Noly, P. E. et al. Reduction of plasma angiopoietin-like 2 after cardiac surgery is related to tissue inflammation and senescence status of patients. J. Thorac. Cardiovasc. Surg. 158, 792–802.e5 (2019). · DOI
  62. Bujak, M. et al. Aging-related defects are associated with adverse cardiac remodeling in a mouse model of reperfused myocardial infarction. J. Am. Coll. Cardiol. 51, 1384–1392 (2008). · DOI
  63. Gude, N. A., Broughton, K. M., Firouzi, F. & Sussman, M. A. Cardiac ageing: extrinsic and intrinsic factors in cellular renewal and senescence. Nat. Rev. Cardiol. 15, 523–542 (2018). · DOI
  64. Nattel, S. Molecular and cellular mechanisms of atrial fibrosis in atrial fibrillation. JACC Clin. Electrophysiol. 3, 425–435 (2017). · DOI
  65. Sawaki, D. et al. Visceral adipose tissue drives cardiac aging through modulation of fibroblast senescence by osteopontin production. Circulation 138, 809–822 (2018). · DOI
  66. Zhu, F. et al. Senescent cardiac fibroblast is critical for cardiac fibrosis after myocardial infarction. PLoS ONE 8, e74535 (2013). · DOI · Paper page
  67. Azar, A., Lawrence, I., Jofre, S., Mell, J. & Sell, C. Distinct patterns of gene expression in human cardiac fibroblasts exposed to rapamycin treatment or methionine restriction. Ann. NY Acad. Sci. 1418, 95–105 (2018). · DOI
  68. Li, W. Q. et al. Calcitonin gene-related peptide inhibits the cardiac fibroblasts senescence in cardiac fibrosis via up-regulating klotho expression. Eur. J. Pharmacol. 843, 96–103 (2019). · DOI
  69. Bonda, T. A. et al. Interleukin-6 affects aging-related changes of the PPARα-PGC-1α axis in the myocardium. J. Interferon Cytokine Res. 37, 513–521 (2017). · DOI
  70. Lyu, G. et al. TGF-β signaling alters H4K20me3 status via miR-29 and contributes to cellular senescence and cardiac aging. Nat. Commun. 9, 2560 (2018). · DOI
  71. Rawal, S. et al. Down-regulation of miR-15a/b accelerates fibrotic remodelling in the type 2 diabetic human and mouse heart. Clin. Sci. 131, 847–863 (2017). · DOI
  72. Lin, R. et al. miR-1468-3p promotes aging-related cardiac fibrosis. Mol. Ther. Nucleic Acids 20, 589–605 (2020). · DOI
  73. Huang, Z. P. & Wang, D. Z. miR-22 in smooth muscle cells: a potential therapy for cardiovascular disease. Circulation 137, 1842–1845 (2018). · DOI
  74. Tijsen, A. J. et al. The microRNA-15 family inhibits the TGFβ-pathway in the heart. Cardiovasc. Res. 104, 61–71 (2014). · DOI
  75. Gutiérrez-Fernández, A. et al. Loss of MT1-MMP causes cell senescence and nuclear defects which can be reversed by retinoic acid. EMBO J. 34, 1875–1888 (2015). · DOI · Paper page
  76. Abdelfatah, N. et al. Characterization of a unique form of arrhythmic cardiomyopathy caused by recessive mutation in LEMD2. JACC Basic Transl. Sci. 4, 204–221 (2019). · DOI
  77. Jia, L. et al. Haplodeficiency of ataxia telangiectasia mutated accelerates heart failure after myocardial infarction. J. Am. Heart Assoc. 6, e006349 (2017). · DOI
  78. Xie, J. et al. Premature senescence of cardiac fibroblasts and atrial fibrosis in patients with atrial fibrillation. Oncotarget 8, 57981–57990 (2017). · DOI
  79. Nakamura, M. & Sadoshima, J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat. Rev. Cardiol. 15, 387–407 (2018). · DOI
  80. Oldfield, C. J., Duhamel, T. A. & Dhalla, N. S. Mechanisms for the transition from physiological to pathological cardiac hypertrophy. Can. J. Physiol. Pharmacol. 98, 74–84 (2020). · DOI
  81. Dai, D. F. et al. Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria. Aging Cell 9, 536–544 (2010). · DOI · Paper page
  82. Cataldi, A. et al. p53 and telomerase control rat myocardial tissue response to hypoxia and ageing. Eur. J. Histochem. 53, 209–216 (2009). · DOI
  83. Li, Y. et al. SIRT3 deficiency exacerbates p53/Parkin-mediated mitophagy inhibition and promotes mitochondrial dysfunction: implication for aged hearts. Int. J. Mol. Med. 41, 3517–3526 (2018).
  84. Zha, Z., Wang, J., Wang, X., Lu, M. & Guo, Y. Involvement of PINK1/Parkin-mediated mitophagy in AGE-induced cardiomyocyte aging. Int. J. Cardiol. 227, 201–208 (2017). · DOI
  85. Dong, R. et al. Bradykinin inhibits oxidative stress-induced cardiomyocytes senescence via regulating redox state. PLoS ONE 8, e77034 (2013). · DOI
  86. Takahashi, K. et al. Premature cardiac senescence in DahlS.Z-Lepr(fa)/Lepr(fa) rats as a new animal model of metabolic syndrome. Nagoya J. Med. Sci. 76, 35–49 (2014).
  87. Ock, S. et al. Deletion of IGF-1 receptors in cardiomyocytes attenuates cardiac aging in male mice. Endocrinology 157, 336–345 (2016). · DOI
  88. Hua, Y. et al. Cathepsin K knockout alleviates aging-induced cardiac dysfunction. Aging Cell 14, 345–351 (2015). · DOI
  89. Sun, R. et al. Senescence as a novel mechanism involved in β-adrenergic receptor mediated cardiac hypertrophy. PLoS ONE 12, e0182668 (2017). · DOI
  90. Sheng, Y. et al. Opposing effects on cardiac function by calorie restriction in different-aged mice. Aging Cell 16, 1155–1167 (2017). · DOI
  91. Louhelainen, M. et al. Effects of calcium sensitizer OR-1986 on a cardiovascular mortality and myocardial remodelling in hypertensive Dahl/Rapp rats. J. Physiol. Pharmacol. 60, 41–47 (2009).
  92. Ewer, M. S. & Ewer, S. M. Cardiotoxicity of anticancer treatments. Nat. Rev. Cardiol. 12, 547–558 (2015). · DOI
  93. Herrmann, J. Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia. Nat. Rev. Cardiol. 17, 474–502 (2020). · DOI · Paper page
  94. Piegari, E. et al. Doxorubicin induces senescence and impairs function of human cardiac progenitor cells. Basic Res. Cardiol. 108, 334 (2013). · DOI
  95. Lazzarini, E. et al. The human amniotic fluid stem cell secretome effectively counteracts doxorubicin-induced cardiotoxicity. Sci. Rep. 6, 29994 (2016). · DOI
  96. Ghosh, A. K. et al. A small molecule inhibitor of PAI-1 protects against doxorubicin-induced cellular senescence. Oncotarget 7, 72443–72457 (2016). · DOI
  97. Altieri, P. et al. Testosterone antagonizes doxorubicin-induced senescence of cardiomyocytes. J. Am. Heart Assoc. 5, e002383 (2016). · DOI
  98. Altieri, P. et al. Inhibition of doxorubicin-induced senescence by PPARδ activation agonists in cardiac muscle cells: cooperation between PPARδ and Bcl6. PLoS ONE 7, e46126 (2012). · DOI
  99. Xia, W. & Hou, M. Mesenchymal stem cells confer resistance to doxorubicin-induced cardiac senescence by inhibiting microRNA-34a. Oncol. Lett. 15, 10037–10046 (2018).
  100. Piegari, E. et al. MicroRNA-34a regulates doxorubicin-induced cardiotoxicity in rat. Oncotarget 7, 62312–62326 (2016). · DOI
  101. Du, W. W. et al. Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses. Eur. Heart J. 38, 1402–1412 (2017).
  102. Xie, Z., Xia, W. & Hou, M. Long intergenic noncoding RNAp21 mediates cardiac senescence via the Wnt/betacatenin signaling pathway in doxorubicin-induced cardiotoxicity. Mol. Med. Rep. 17, 2695–2704 (2018).
  103. Kim, E. J. et al. Involvement of corin downregulation in ionizing radiation-induced senescence of myocardial cells. Int. J. Mol. Med. 35, 731–738 (2015). · DOI
  104. Saleh, Y., Abdelkarim, O., Herzallah, K. & Abela, G. S. Anthracycline-induced cardiotoxicity: mechanisms of action, incidence, risk factors, prevention, and treatment. Heart Fail Rev. 26, 1159–1173 (2021). · DOI
  105. Braunwald, E. Biomarkers in heart failure. N. Engl. J. Med. 358, 2148–2159 (2008). · DOI
  106. Din, S. et al. Metabolic dysfunction consistent with premature aging results from deletion of pim kinases. Circ. Res. 115, 376–387 (2014). · DOI
  107. Inuzuka, Y. et al. Suppression of phosphoinositide 3-kinase prevents cardiac aging in mice. Circulation 120, 1695–1703 (2009). · DOI
  108. Bertagnolli, M. et al. Transient neonatal high oxygen exposure leads to early adult cardiac dysfunction, remodeling, and activation of the Renin-Angiotensin system. Hypertension 63, 143–150 (2014). · DOI
  109. Caragnano, A. et al. Autophagy and inflammasome activation in dilated cardiomyopathy. J. Clin. Med. 8, 1519 (2019). · DOI
  110. Neves, M. F., Cunha, A. R., Cunha, M. R., Gismondi, R. A. & Oigman, W. The role of renin-angiotensin-aldosterone system and its new components in arterial stiffness and vascular aging. High Blood Press. Cardiovasc. Prev. 25, 137–145 (2018). · DOI
  111. Minamino, T. & Komuro, I. Vascular cell senescence: contribution to atherosclerosis. Circ. Res. 100, 15–26 (2007). · DOI · Paper page
  112. Jia, K. et al. Senolytic agent navitoclax inhibits angiotensin II-induced heart failure in mice. J. Cardiovasc. Pharmacol. 76, 452–460 (2020). · DOI
  113. Sciarretta, S., Maejima, Y., Zablocki, D. & Sadoshima, J. The role of autophagy in the heart. Annu. Rev. Physiol. 80, 1–26 (2018). · DOI · Paper page
  114. Russomanno, G. et al. The anti-ageing molecule sirt1 mediates beneficial effects of cardiac rehabilitation. Immun. Ageing 14, 7 (2017). · DOI
  115. Youn, J. C. et al. Increased frequency of CD4+CD57+ senescent T cells in patients with newly diagnosed acute heart failure: exploring new pathogenic mechanisms with clinical relevance. Sci. Rep. 9, 12887 (2019). · DOI
  116. Toldo, S. & Abbate, A. The NLRP3 inflammasome in acute myocardial infarction. Nat. Rev. Cardiol. 15, 203–214 (2018). · DOI
  117. Frangogiannis, N. G. Pathophysiology of myocardial infarction. Compr. Physiol. 5, 1841–1875 (2015). · DOI
  118. Boon, R. A. & Dimmeler, S. MicroRNAs in myocardial infarction. Nat. Rev. Cardiol. 12, 135–142 (2015). · DOI
  119. Rodriguez, J. A. et al. Selective increase of cardiomyocyte derived extracellular vesicles after experimental myocardial infarction and functional effects on the endothelium. Thrombosis Res. 170, 1–9 (2018). · DOI
  120. Nishimura, A. et al. Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence. Sci. Signal. 11, eaat5185 (2018). · DOI
  121. Lin, B., Feng, D. & Xu, J. Cardioprotective effects of microRNA-18a on acute myocardial infarction by promoting cardiomyocyte autophagy and suppressing cellular senescence via brain derived neurotrophic factor. Cell Biosci. 9, 38 (2019). · DOI
  122. Louhelainen, M. et al. Oral levosimendan prevents postinfarct heart failure and cardiac remodeling in diabetic Goto-Kakizaki rats. J. Hypertens. 27, 2094–2107 (2009). · DOI
  123. Wen, Z., Mai, Z., Chen, Y., Wang, J. F. & Geng, D. F. Angiotensin II receptor blocker reverses heart failure by attenuating local oxidative stress and preserving resident stem cells in rats with myocardial infarction. Am. J. Transl. Res. 10, 2387–2401 (2018).
  124. Shibamoto, M. et al. Activation of dna damage response and cellular senescence in cardiac fibroblasts limit cardiac fibrosis after myocardial infarction. Int. Heart J. 60, 944–957 (2019). · DOI
  125. Du, G. Q. et al. Targeted myocardial delivery of GDF11 gene rejuvenates the aged mouse heart and enhances myocardial regeneration after ischemia-reperfusion injury. Basic Res. Cardiol. 112, 7 (2017). · DOI
  126. Andrade, J., Khairy, P., Dobrev, D. & Nattel, S. The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms. Circ. Res. 114, 1453–1468 (2014). · DOI
  127. Jesel, L. et al. Atrial fibrillation progression is associated with cell senescence burden as determined by p53 and p16 expression. J. Clin. Med. 9, 36 (2019). · DOI
  128. Aharonov, A. et al. ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration. Nat. Cell Biol. 22, 1346–1356 (2020). · DOI
  129. Yutzey, K. E. Cardiomyocyte proliferation: teaching an old dogma new tricks. Circ. Res. 120, 627–629 (2017). · DOI
  130. Rubin, N., Harrison, M. R., Krainock, M., Kim, R. & Lien, C. L. Recent advancements in understanding endogenous heart regeneration-insights from adult zebrafish and neonatal mice. Semin. Cell Dev. Biol. 58, 34–40 (2016). · DOI
  131. Eschenhagen, T. et al. Cardiomyocyte regeneration: a consensus statement. Circulation 136, 680–686 (2017). · DOI
  132. He, L., Nguyen, N. B., Ardehali, R. & Zhou, B. Heart regeneration by endogenous stem cells and cardiomyocyte proliferation: controversy, fallacy, and progress. Circulation 142, 275–291 (2020). · DOI
  133. Menasché, P. Cell therapy trials for heart regeneration - lessons learned and future directions. Nat. Rev. Cardiol. 15, 659–671 (2018). · DOI
  134. Zhang, M. et al. Bone marrow mesenchymal stem cell transplantation retards the natural senescence of rat hearts. Stem Cell Transl. Med. 4, 494–502 (2015). · DOI
  135. Song, H. F. et al. Aged human multipotent mesenchymal stromal cells can be rejuvenated by neuron-derived neurotrophic factor and improve heart function after injury. JACC Basic Transl. Sci. 2, 702–716 (2017). · DOI
  136. Khan, M., Mohsin, S., Khan, S. N. & Riazuddin, S. Repair of senescent myocardium by mesenchymal stem cells is dependent on the age of donor mice. J. Cell. Mol. Med. 15, 1515–1527 (2011). · DOI
  137. Lewis-McDougall, F. C. et al. Aged-senescent cells contribute to impaired heart regeneration. Aging Cell 18, e12931 (2019). · DOI · Paper page
  138. Khatiwala, R. V. et al. Inhibition of p16INK4A to rejuvenate aging human cardiac progenitor cells via the upregulation of anti-oxidant and NFκB signal pathways. Stem Cell Rev. Rep. 14, 612–625 (2018). · DOI
  139. Hariharan, N. et al. Nucleostemin rejuvenates cardiac progenitor cells and antagonizes myocardial aging. J. Am. Coll. Cardiol. 65, 133–147 (2015). · DOI
  140. Matsumoto, C. et al. Short telomeres induce p53 and autophagy and modulate age-associated changes in cardiac progenitor cell fate. Stem Cell 36, 868–880 (2018). · DOI
  141. Castaldi, A. et al. Decline in cellular function of aged mouse c-kit+ cardiac progenitor cells. J. Physiol. 595, 6249–6262 (2017). · DOI
  142. Fomison-Nurse, I. et al. Diabetes induces the activation of pro-ageing MIR-34a in the heart, but has differential effects on cardiomyocytes and cardiac progenitor cells. Cell Death Differ. 25, 1336–1349 (2018). · DOI
  143. Toko, H. et al. Differential regulation of cellular senescence and differentiation by prolyl isomerase Pin1 in cardiac progenitor cells. J. Biol. Chem. 289, 5348–5356 (2014). · DOI
  144. Zhao, L. et al. TERT assists GDF11 to rejuvenate senescent VEGFR2+/CD133+ cells in elderly patients with myocardial infarction. Lab. Invest. 99, 1661–1688 (2019). · DOI
  145. Hong, Y. et al. miR-155-5p inhibition rejuvenates aged mesenchymal stem cells and enhances cardioprotection following infarction. Aging Cell 19, e13128 (2020). · DOI
  146. Choudhery, M. S. et al. Mesenchymal stem cells conditioned with glucose depletion augments their ability to repair-infarcted myocardium. J. Cell. Mol. Med. 16, 2518–2529 (2012). · DOI
  147. Samse, K. et al. Functional effect of Pim1 depends upon intracellular localization in human cardiac progenitor cells. J. Biol. Chem. 290, 13935–13947 (2015). · DOI
  148. Rafatian, G. et al. Mybl2 rejuvenates heart explant-derived cells from aged donors after myocardial infarction. Aging Cell 19, e13174 (2020). · DOI
  149. Dong, J. et al. MiR-10a rejuvenates aged human mesenchymal stem cells and improves heart function after myocardial infarction through KLF4. Stem Cell Res. Ther. 9, 151 (2018). · DOI
  150. Mohsin, S. et al. Rejuvenation of human cardiac progenitor cells with pim-1 kinase. Circ. Res. 113, 1169–1179 (2013). · DOI
  151. Fu, C. et al. Bradykinin protects cardiac c-kit positive cells from high-glucose-induced senescence through B2 receptor signaling pathway. J. Cell. Biochem. 120, 17731–17743 (2019). · DOI
  152. Nakamura, T. et al. Age-related increase in Wnt inhibitor causes a senescence-like phenotype in human cardiac stem cells. Biochem. Biophys. Res. Commun. 487, 653–659 (2017). · DOI
  153. Leone, M. & Engel, F. B. Advances in heart regeneration based on cardiomyocyte proliferation and regenerative potential of binucleated cardiomyocytes and polyploidization. Clin. Sci. 133, 1229–1253 (2019). · DOI
  154. Sarig, R. et al. Transient p53-mediated regenerative senescence in the injured heart. Circulation 139, 2491–2494 (2019). · DOI
  155. Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995). · DOI · Paper page
  156. Ritschka, B. et al. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev. 31, 172–183 (2017). · DOI · Paper page
  157. Muñoz-Espín, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013). · DOI · Paper page
  158. Zhu, Y. et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 15, 428–435 (2016). · DOI · Paper page

Cited by

Sorted by citations

See all 304

Metadata

Authors
Mehdizadeh, M., Aguilar, M., Thorin, E., Ferbeyre, G., & Nattel, S.
ORCID
Venue
Nature Reviews Cardiology
Publisher
Springer Science and Business Media LLC
Published
2021-10-19
Volume
19
Issue
4
Pages
250-264
ISSN
  • 1759-5002
  • 1759-5010
DOI
10.1038/s41569-021-00624-2
Cited by
304
References
49
Language
en
Licence

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review