Length‐independent telomere damage drives post‐mitotic cardiomyocyte senescence

Published on Mar 1, 2019in The EMBO Journal11.227
· DOI :10.15252/embj.2018100492
Rhys Anderson8
Estimated H-index: 8
(Newcastle University),
Anthony B. Lagnado5
Estimated H-index: 5
(Newcastle University)
+ 31 AuthorsJoão F. Passos35
Estimated H-index: 35
(Newcastle University)
Abstract Ageing is the biggest risk factor for cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age‐related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post‐mitotic cardiomyocytes and investigate whether clearance of senescent cells attenuates age‐related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent‐like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction and crucially can occur independently of cell division and telomere length. Length‐independent telomere damage in cardiomyocytes activates the classical senescence‐inducing pathways, p21 CIP and p16 INK4a , and results in a non‐canonical senescence‐associated secretory phenotype, which is pro‐fibrotic and pro‐hypertrophic. Pharmacological or genetic clearance of senescent cells in mice alleviates detrimental features of cardiac ageing, including myocardial hypertrophy and fibrosis. Our data describe a mechanism by which senescence can occur and contribute to age‐related myocardial dysfunction and in the wider setting to ageing in post‐mitotic tissues.
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