Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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 the management of patients with heart disease.

Key points

  • Cellular senescence refers to the set of changes noted in cells damaged by various stress factors such as dysfunctional telomeres, DNA damage and expression of certain oncogenes, which also occur in cells of aged individuals.

  • Senescent cells have the potential to influence neighbouring cells through secreted cytokines, chemokines, matrix remodelling proteases, growth factors and lipids, collectively referred to as the senescence-associated secretory phenotype.

  • Senescent cells that are transiently present in the heart in response to temporary stress can be beneficial, whereas the long-term accumulation of senescent cells can impair heart function and promote cardiac disease.

  • Acute cellular senescence has important physiological roles in heart development and regeneration; however, senescent cells accumulate progressively in the heart during ageing and cause an age-related decline in heart function.

  • Therapeutic interventions that target senescent cells have the potential to attenuate cardiac dysfunction and improve disease outcomes.

  • Despite a growing number of studies investigating the role of senescence in cardiac ageing and disease, important knowledge gaps remain, especially related to the potential therapeutic benefits of targeting cellular senescence.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Milestones in cellular senescence research.
Fig. 2: Overview of molecular mechanisms leading to cellular senescence.
Fig. 3: Intercellular paracrine communication between different cardiac cell types via SASP.
Fig. 4: Involvement of cellular senescence in the pathogenesis of cardiac disease.
Fig. 5: Therapeutic strategies for targeting cellular senescence in ageing or diseased hearts.
Fig. 6: Molecular mechanisms underlying the therapeutic clearance of senescent cells and SASP modulation.

References

  1. 1.

    López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  2. 2.

    Kuilman, T., Michaloglou, C., Mooi, W. J. & Peeper, D. S. The essence of senescence. Genes Dev. 24, 2463–2479 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685–705 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Shimizu, I. & Minamino, T. Cellular senescence in cardiac diseases. J. Cardiol. 74, 313–319 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Storer, M. et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119–1130 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Kennedy, B. K. et al. Geroscience: linking aging to chronic disease. Cell 159, 709–713 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Paez-Ribes, M., Gonzalez-Gualda, E., Doherty, G. J. & Munoz-Espin, D. Targeting senescent cells in translational medicine. EMBO Mol. Med. 11, e10234 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Farr, J. N. et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23, 1072–1079 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Musi, N. et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17, e12840 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. 14.

    Roos, C. M. et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 15, 973–977 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Xu, M. et al. Targeting senescent cells enhances adipogenesis and metabolic function in old age. eLife 4, e12997 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Xu, E. & Wen, H. X. Risk factors of cerebrovascular diseases and their intervention and management. Chin. J. Contemp. Neurol. Neurosurg. 15, 20–26 (2015).

    Google Scholar 

  17. 17.

    Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Weissman, A. Essays upon Heredity and Kindred Biological Problems (Clarendon, 1891).

  21. 21.

    Levine, H. J. Rest heart rate and life expectancy. J. Am. Coll. Cardiol. 30, 1104–1106 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    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).

    PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Greider, C. W. & Blackburn, E. H. The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity. Cell 51, 887–898 (1987).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Chang, E. & Harley, C. B. Telomere length and replicative aging in human vascular tissues. Proc. Natl Acad. Sci. USA 92, 11190–11194 (1995).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Razgonova, M. P. et al. Telomerase and telomeres in aging theory and chronographic aging theory (Review). Mol. Med. Rep. 22, 1679–1694 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Mallette, F. A. & Ferbeyre, G. The DNA damage signaling pathway connects oncogenic stress to cellular senescence. Cell Cycle 6, 1831–1836 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Gorgoulis, V. et al. Cellular senescence: defining a path forward. Cell 179, 813–827 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Anderson, R. et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 38, e100492 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35.

    Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Bussian, T. J. et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578–582 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Hickson, L. J. et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine 47, 446–456 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Justice, J. N. et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine 40, 554–563 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Munoz-Espin, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Jun, J. I. & Lau, L. F. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat. Cell Biol. 12, 676–685 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Feng, T. et al. CCN1-induced cellular senescence promotes heart regeneration. Circulation 139, 2495–2498 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

    Grosse, L. et al. Defined p16(High) senescent cell types are indispensable for mouse healthspan. Cell Metab. 32, 87–99.e6 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Deschênes-Simard, X. et al. Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation. Genes Dev. 27, 900–915 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  46. 46.

    Tran, D. et al. Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence. Aging Cell 13, 669–678 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Bueno, M. et al. Mitochondria, aging, and cellular senescence: implications for scleroderma. Curr. Rheumatol. Rep. 22, 37 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Nacarelli, T., Azar, A. & Sell, C. Mitochondrial stress induces cellular senescence in an mTORC1-dependent manner. Free Radic. Biol. Med. 95, 133–154 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  49. 49.

    Chapman, J., Fielder, E. & Passos, J. F. Mitochondrial dysfunction and cell senescence: deciphering a complex relationship. FEBS Lett. 593, 1566–1579 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Sahin, E. et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470, 359–365 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Ito, T., Yagi, S. & Yamakuchi, M. MicroRNA-34a regulation of endothelial senescence. Biochem. Biophys. Res. Commun. 398, 735–740 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. 53.

    Jazbutyte, V. et al. MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart. Age 35, 747–762 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Bilsland, A. E., Revie, J. & Keith, W. MicroRNA and senescence: the senectome, integration and distributed control. Crit. Rev. Oncog. 18, 373–390 (2013).

    PubMed  Article  PubMed Central  Google Scholar 

  55. 55.

    Yosef, R. et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat. Commun. 7, 11190 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Ahn, J. S. et al. Aging-associated increase of gelsolin for apoptosis resistance. Biochem. Biophys. Res. Commun. 312, 1335–1341 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. 57.

    d’Adda di Fagagna, F. Living on a break: cellular senescence as a DNA-damage response. Nat. Rev. Cancer 8, 512–522 (2008).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  58. 58.

    Baar, M. P. et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 169, 132–147.e16 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Coppe, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

    Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. 61.

    Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  62. 62.

    Childs, B. G., Durik, M., Baker, D. J. & van Deursen, J. M. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat. Med. 21, 1424–1435 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Martini, H. et al. Aging induces cardiac mesenchymal stromal cell senescence and promotes endothelial cell fate of the CD90+ subset. Aging Cell 18, e13015 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  64. 64.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. 65.

    Matsushita, H. et al. eNOS activity is reduced in senescent human endothelial cells: preservation by hTERT immortalization. Circ. Res. 89, 793–798 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Bochenek, M. L., Schütz, E. & Schäfer, K. Endothelial cell senescence and thrombosis: ageing clots. Thromb. Res. 147, 36–45 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67.

    Tang, X., Li, P. H. & Chen, H. Z. Cardiomyocyte senescence and cellular communications within myocardial microenvironments. Front. Endocrinol. 11, 280 (2020).

    Article  Google Scholar 

  68. 68.

    Li, H. et al. Targeting age-related pathways in heart failure. Circ. Res. 126, 533–551 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Franceschi, C. et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. NY Acad. Sci. 908, 244–254 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  71. 71.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    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).

    PubMed  PubMed Central  Google Scholar 

  73. 73.

    van Deursen, J. M. The role of senescent cells in ageing. Nature 509, 439–446 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. 74.

    He, S. & Sharpless, N. E. Senescence in health and disease. Cell 169, 1000–1011 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Jeon, O. H. et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775–781 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Palmer, A. K. et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell 18, e12950 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  78. 78.

    Robbins, P. D. et al. Senolytic drugs: reducing senescent cell viability to extend health span. Annu. Rev. Pharmacol. Toxicol. 61, 779–803 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  79. 79.

    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).

    PubMed  Article  PubMed Central  Google Scholar 

  80. 80.

    Cianflone, E. et al. Targeting cardiac stem cell senescence to treat cardiac aging and disease. Cells 9, 1558 (2020).

    CAS  PubMed Central  Article  Google Scholar 

  81. 81.

    Moiseeva, O., Deschênes-Simard, X., Pollak, M. & Ferbeyre, G. Metformin, aging and cancer. Aging 5, 330–331 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Di Micco, R., Krizhanovsky, V., Baker, D. & d’Adda di Fagagna, F. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat. Rev. Mol. Cell Biol. 22, 75–95 (2021).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  83. 83.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Noren Hooten, N. et al. Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence. Aging Cell 15, 572–581 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Macip, S. et al. Inhibition of p21-mediated ROS accumulation can rescue p21-induced senescence. EMBO J. 21, 2180–2188 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Kosugi, R. et al. Angiotensin II receptor antagonist attenuates expression of aging markers in diabetic mouse heart. Circ. J. 70, 482–488 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  87. 87.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  88. 88.

    Baker, D. J. et al. Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Cui, S. et al. Postinfarction hearts are protected by premature senescent cardiomyocytes via GATA4-dependent CCN1 secretion. J. Am. Heart Assoc. 7, e009111 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  93. 93.

    von Zglinicki, T., Wan, T. & Miwa, S. Senescence in post-mitotic cells: a driver of aging? Antioxid. Redox Signal. 34, 308–323 (2021).

    Article  CAS  Google Scholar 

  94. 94.

    Sapieha, P. & Mallette, F. A. Cellular senescence in postmitotic cells: beyond growth arrest. Trends Cell Biol. 28, 595–607 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  95. 95.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Wu, Y. et al. Pax8 plays a pivotal role in regulation of cardiomyocyte growth and senescence. J. Cell. Mol. Med. 20, 644–654 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    North, B. J. & Sinclair, D. A. The intersection between aging and cardiovascular disease. Circ. Res. 110, 1097–1108 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    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).

    PubMed  Article  PubMed Central  Google Scholar 

  101. 101.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  103. 103.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    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).

    PubMed  Article  PubMed Central  Google Scholar 

  105. 105.

    Nattel, S. Molecular and cellular mechanisms of atrial fibrosis in atrial fibrillation. JACC Clin. Electrophysiol. 3, 425–435 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  106. 106.

    Sawaki, D. et al. Visceral adipose tissue drives cardiac aging through modulation of fibroblast senescence by osteopontin production. Circulation 138, 809–822 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  107. 107.

    Meyer, K., Hodwin, B., Ramanujam, D., Engelhardt, S. & Sarikas, A. Essential role for premature senescence of myofibroblasts in myocardial fibrosis. J. Am. Coll. Cardiol. 67, 2018–2028 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  108. 108.

    Zhu, F. et al. Senescent cardiac fibroblast is critical for cardiac fibrosis after myocardial infarction. PLoS ONE 8, e74535 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  110. 110.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  111. 111.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  112. 112.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  113. 113.

    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).

    CAS  Article  Google Scholar 

  114. 114.

    Lin, R. et al. miR-1468-3p promotes aging-related cardiac fibrosis. Mol. Ther. Nucleic Acids 20, 589–605 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Huang, Z. P. & Wang, D. Z. miR-22 in smooth muscle cells: a potential therapy for cardiovascular disease. Circulation 137, 1842–1845 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Tijsen, A. J. et al. The microRNA-15 family inhibits the TGFβ-pathway in the heart. Cardiovasc. Res. 104, 61–71 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  117. 117.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  118. 118.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    Jia, L. et al. Haplodeficiency of ataxia telangiectasia mutated accelerates heart failure after myocardial infarction. J. Am. Heart Assoc. 6, e006349 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Xie, J. et al. Premature senescence of cardiac fibroblasts and atrial fibrosis in patients with atrial fibrillation. Oncotarget 8, 57981–57990 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Nakamura, M. & Sadoshima, J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat. Rev. Cardiol. 15, 387–407 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  122. 122.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  123. 123.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  124. 124.

    Morin, D. et al. Hsp22 overexpression induces myocardial hypertrophy, senescence and reduced life span through enhanced oxidative stress. Free Radic. Biol. Med. 137, 194–200 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  125. 125.

    Cataldi, A. et al. p53 and telomerase control rat myocardial tissue response to hypoxia and ageing. Eur. J. Histochem. 53, 209–216 (2009).

    CAS  Article  Google Scholar 

  126. 126.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    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).

    PubMed  Article  PubMed Central  Google Scholar 

  128. 128.

    Dong, R. et al. Bradykinin inhibits oxidative stress-induced cardiomyocytes senescence via regulating redox state. PLoS ONE 8, e77034 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    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).

    PubMed  PubMed Central  Google Scholar 

  130. 130.

    Ock, S. et al. Deletion of IGF-1 receptors in cardiomyocytes attenuates cardiac aging in male mice. Endocrinology 157, 336–345 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  131. 131.

    Hua, Y. et al. Cathepsin K knockout alleviates aging-induced cardiac dysfunction. Aging Cell 14, 345–351 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Sun, R. et al. Senescence as a novel mechanism involved in β-adrenergic receptor mediated cardiac hypertrophy. PLoS ONE 12, e0182668 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  133. 133.

    Sheng, Y. et al. Opposing effects on cardiac function by calorie restriction in different-aged mice. Aging Cell 16, 1155–1167 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Ewer, M. S. & Ewer, S. M. Cardiotoxicity of anticancer treatments. Nat. Rev. Cardiol. 12, 547–558 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  136. 136.

    Herrmann, J. Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia. Nat. Rev. Cardiol. 17, 474–502 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  137. 137.

    Piegari, E. et al. Doxorubicin induces senescence and impairs function of human cardiac progenitor cells. Basic Res. Cardiol. 108, 334 (2013).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  138. 138.

    Lazzarini, E. et al. The human amniotic fluid stem cell secretome effectively counteracts doxorubicin-induced cardiotoxicity. Sci. Rep. 6, 29994 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    Werner, C. et al. Effects of physical exercise on myocardial telomere-regulating proteins, survival pathways, and apoptosis. J. Am. Coll. Cardiol. 52, 470–482 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  140. 140.

    Ghosh, A. K. et al. A small molecule inhibitor of PAI-1 protects against doxorubicin-induced cellular senescence. Oncotarget 7, 72443–72457 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Altieri, P. et al. Testosterone antagonizes doxorubicin-induced senescence of cardiomyocytes. J. Am. Heart Assoc. 5, e002383 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. 143.

    Xia, W. & Hou, M. Mesenchymal stem cells confer resistance to doxorubicin-induced cardiac senescence by inhibiting microRNA-34a. Oncol. Lett. 15, 10037–10046 (2018).

    PubMed  PubMed Central  Google Scholar 

  144. 144.

    Piegari, E. et al. MicroRNA-34a regulates doxorubicin-induced cardiotoxicity in rat. Oncotarget 7, 62312–62326 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  146. 146.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  148. 148.

    Alessio, N. et al. Increase of circulating IGFBP-4 following genotoxic stress and its implication for senescence. eLife 9, e54523 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. 149.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  150. 150.

    Braunwald, E. Biomarkers in heart failure. N. Engl. J. Med. 358, 2148–2159 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  151. 151.

    Din, S. et al. Metabolic dysfunction consistent with premature aging results from deletion of pim kinases. Circ. Res. 115, 376–387 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. 152.

    Inuzuka, Y. et al. Suppression of phosphoinositide 3-kinase prevents cardiac aging in mice. Circulation 120, 1695–1703 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  153. 153.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  154. 154.

    Rota, M. et al. Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene. Circ. Res. 99, 42–52 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  155. 155.

    Caragnano, A. et al. Autophagy and inflammasome activation in dilated cardiomyopathy. J. Clin. Med. 8, 1519 (2019).

    CAS  PubMed Central  Article  Google Scholar 

  156. 156.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  157. 157.

    Minamino, T. & Komuro, I. Vascular cell senescence: contribution to atherosclerosis. Circ. Res. 100, 15–26 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  158. 158.

    Jia, K. et al. Senolytic agent navitoclax inhibits angiotensin II-induced heart failure in mice. J. Cardiovasc. Pharmacol. 76, 452–460 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  159. 159.

    Sciarretta, S., Maejima, Y., Zablocki, D. & Sadoshima, J. The role of autophagy in the heart. Annu. Rev. Physiol. 80, 1–26 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  160. 160.

    Russomanno, G. et al. The anti-ageing molecule sirt1 mediates beneficial effects of cardiac rehabilitation. Immun. Ageing 14, 7 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  161. 161.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  162. 162.

    Toldo, S. & Abbate, A. The NLRP3 inflammasome in acute myocardial infarction. Nat. Rev. Cardiol. 15, 203–214 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  163. 163.

    Frangogiannis, N. G. Pathophysiology of myocardial infarction. Compr. Physiol. 5, 1841–1875 (2015).

    PubMed  Article  Google Scholar 

  164. 164.

    Boon, R. A. & Dimmeler, S. MicroRNAs in myocardial infarction. Nat. Rev. Cardiol. 12, 135–142 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  165. 165.

    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).

    CAS  Article  Google Scholar 

  166. 166.

    Walaszczyk, A. et al. Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction. Aging Cell 18, e12945 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  167. 167.

    Nishimura, A. et al. Hypoxia-induced interaction of filamin with Drp1 causes mitochondrial hyperfission-associated myocardial senescence. Sci. Signal. 11, eaat5185 (2018).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  168. 168.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  169. 169.

    Louhelainen, M. et al. Oral levosimendan prevents postinfarct heart failure and cardiac remodeling in diabetic Goto-Kakizaki rats. J. Hypertens. 27, 2094–2107 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  170. 170.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  172. 172.

    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).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  173. 173.

    Dookun, E. et al. Clearance of senescent cells during cardiac ischemia-reperfusion injury improves recovery. Aging Cell 19, e13249 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. 174.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  175. 175.

    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).

    PubMed Central  Article  CAS  Google Scholar 

  176. 176.

    Aharonov, A. et al. ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration. Nat. Cell Biol. 22, 1346–1356 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  177. 177.

    Yutzey, K. E. Cardiomyocyte proliferation: teaching an old dogma new tricks. Circ. Res. 120, 627–629 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  178. 178.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  179. 179.

    Eschenhagen, T. et al. Cardiomyocyte regeneration: a consensus statement. Circulation 136, 680–686 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  180. 180.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  181. 181.

    Menasché, P. Cell therapy trials for heart regeneration - lessons learned and future directions. Nat. Rev. Cardiol. 15, 659–671 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  182. 182.

    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).

    CAS  Article  Google Scholar 

  183. 183.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  184. 184.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  185. 185.

    Zhang, Y. et al. Macrophage migration inhibitory factor rejuvenates aged human mesenchymal stem cells and improves myocardial repair. Aging 11, 12641–12660 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  186. 186.

    Lewis-McDougall, F. C. et al. Aged-senescent cells contribute to impaired heart regeneration. Aging Cell 18, e12931 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  187. 187.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  188. 188.

    Hariharan, N. et al. Nucleostemin rejuvenates cardiac progenitor cells and antagonizes myocardial aging. J. Am. Coll. Cardiol. 65, 133–147 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  189. 189.

    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).

    CAS  Article  Google Scholar 

  190. 190.

    Castaldi, A. et al. Decline in cellular function of aged mouse c-kit+ cardiac progenitor cells. J. Physiol. 595, 6249–6262 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  191. 191.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  192. 192.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  193. 193.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  194. 194.

    Hong, Y. et al. miR-155-5p inhibition rejuvenates aged mesenchymal stem cells and enhances cardioprotection following infarction. Aging Cell 19, e13128 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  195. 195.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  196. 196.

    Samse, K. et al. Functional effect of Pim1 depends upon intracellular localization in human cardiac progenitor cells. J. Biol. Chem. 290, 13935–13947 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  197. 197.

    Rafatian, G. et al. Mybl2 rejuvenates heart explant-derived cells from aged donors after myocardial infarction. Aging Cell 19, e13174 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  198. 198.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  199. 199.

    Mohsin, S. et al. Rejuvenation of human cardiac progenitor cells with pim-1 kinase. Circ. Res. 113, 1169–1179 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  200. 200.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  201. 201.

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  202. 202.

    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).

    CAS  Article  Google Scholar 

  203. 203.

    Sarig, R. et al. Transient p53-mediated regenerative senescence in the injured heart. Circulation 139, 2491–2494 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  204. 204.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  205. 205.

    Hoenicke, L. & Zender, L. Immune surveillance of senescent cells — biological significance in cancer- and non-cancer pathologies. Carcinogenesis 33, 1123–1126 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  206. 206.

    Ritschka, B. et al. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev. 31, 172–183 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  207. 207.

    Muñoz-Espín, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  208. 208.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

The authors thank L. Lefebvre (Montreal Heart Institute, Canada) for valuable secretarial help with manuscript preparation and submission. The authors received funding from the Canadian Institutes of Health Research (grant 148401 to S.N.; grants 166110 and 162446 to E.T.), Heart and Stroke Foundation of Canada (18-0022032 to S.N.), the Montreal Heart Institute Foundation (S.N. and E.T.) and a doctoral training scholarship from the Fonds de Recherche en Santé du Québec (M.M.).

Review criteria

This Review includes an introductory narrative section, followed by a systematic review of the role of cellular senescence in heart disease. Electronic databases, including Medline, Scopus and the Cochrane library, were searched with the following search formula: (“senescence” OR “senescent” OR “SASP”) [title/abstract] AND (“heart” OR “cardiac”) [title/abstract]. Only papers with English full texts were reviewed. The primary search results were screened based on their abstracts to find potentially relevant studies; only studies in which more than one marker of senescence (Box 1) were used to identify senescent cells were included. In many excluded papers, the term ‘senescence’ was used synonymously with the ageing process, without defining senescence per se. Articles were selected based on the exploration of a role for cell senescence in cardiac development, physiology and/or disease. The full texts of the selected articles were then checked by two independent investigators, and final articles were chosen by consensus to form the primary literature base for this Review. A limited number of additional citations were included if needed to support or detail a key concept related to the selected literature. A consort diagram of the systematic search approach and results is available as Supplementary Figure 1.

Author information

Affiliations

Authors

Contributions

M.M. researched data for the article. M.M., M.A., E.T., G.F. and S.N. wrote the manuscript. All the authors contributed to discussion of the content and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Stanley Nattel.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Cardiology thanks G. Ellison-Hughes and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Senolytics

Therapeutic compounds that kill senescent cells.

Telomerase

Enzyme responsible for the maintenance of telomere length by the addition of telomere repeat sequences to the end of telomeres.

Telomere

A specific complex at the end of linear eukaryotic chromosomes consisting of repeat DNA sequences and associated proteins; critically short telomeres cause cellular senescence.

Immunosenescence

Senescence of the immune cells that are responsible for recognizing and eliminating senescent cells.

microRNAs

(miRNAs). Endogenous small RNAs that regulate gene expression.

PML nuclear bodies

Promyelocytic leukaemia protein (PML) nuclear bodies are membraneless structures located in the nucleus of eukaryotic cells and are involved in DNA damage, DNA repair, telomere homeostasis and p53-associated apoptosis.

INK-ATTAC

Transgenic mouse model in which senescent cells express a ‘suicide’ gene (Casp8, encoding caspase 8) and undergo apoptosis following the treatment of mice with a polymerizing agent (AP20187) that activates caspase.

p16-3MR

Transgenic mouse model in which senescent cells express the herpes simplex virus thymidine kinase and can therefore be eliminated following the treatment of mice with ganciclovir.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mehdizadeh, M., Aguilar, M., Thorin, E. et al. The role of cellular senescence in cardiac disease: basic biology and clinical relevance. Nat Rev Cardiol (2021). https://doi.org/10.1038/s41569-021-00624-2

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing