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.
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.
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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.).
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.
The authors declare no competing interests.
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Therapeutic compounds that kill senescent cells.
Enzyme responsible for the maintenance of telomere length by the addition of telomere repeat sequences to the end of telomeres.
A specific complex at the end of linear eukaryotic chromosomes consisting of repeat DNA sequences and associated proteins; critically short telomeres cause cellular senescence.
Senescence of the immune cells that are responsible for recognizing and eliminating senescent cells.
(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.
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.
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.
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Mehdizadeh, M., Aguilar, M., Thorin, E. et al. The role of cellular senescence in cardiac disease: basic biology and clinical relevance. Nat Rev Cardiol 19, 250–264 (2022). https://doi.org/10.1038/s41569-021-00624-2
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