Resumen de Length‐independent telomere damage drives post‐mitotic cardiomyocyte senescence
Rhys Anderson, Anthony Lagnado, Damien Maggiorani, Anna Walaszczyk, Emily Dookun, James Chapman, Jodie Birch, Hanna Salmonowicz, Mikolaj Ogrodnik, Diana Jurk, Carole Proctor, Clara Correia‐Melo, Stella Victorelli, Edward Fielder, Rolando Berlinguer‐Palmini, Andrew Owens, Laura Greaves, Kathy L Kolsky, Angelo Parini, Victorine Douin‐Echinard, Nathan K. LeBrasseur, Helen M. Arthur, Simon Tual‐Chalot, Marissa J. Schafer, Carolyn M. Roos, Jordan D. Miller, Neil Robertson, Jelena Mann, Peter D. Adams, Tamara Tchkonia, James L. Kirkland, Jeanne Mialet‐Perez, G. D. Richardson, João F. Passos
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, p21CIP and p16INK4a, 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.
