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 C. Greaves, Kathy L. Kolsky, Angelo Parini, Victorine Douin-EchinardNathan 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, Gavin D. Richardson, João F. Passos

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

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.

Original languageEnglish (US)
Article numbere100492
JournalEMBO Journal
Volume38
Issue number5
DOIs
StatePublished - Mar 1 2019

Keywords

  • ageing
  • cardiomyocytes
  • senescence
  • senolytics
  • telomeres

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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