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Length‐independent telomere damage drives post‐mitotic cardiomyocyte senescence
Author(s) -
Anderson Rhys,
Lagnado Anthony,
Maggiorani Damien,
Walaszczyk Anna,
Dookun Emily,
Chapman James,
Birch Jodie,
Salmonowicz Hanna,
Ogrodnik Mikolaj,
Jurk Diana,
Proctor Carole,
CorreiaMelo Clara,
Victorelli Stella,
Fielder Edward,
BerlinguerPalmini Rolando,
Owens Andrew,
Greaves Laura C,
Kolsky Kathy L,
Parini Angelo,
DouinEchinard Victorine,
LeBrasseur Nathan K,
Arthur Helen M,
TualChalot Simon,
Schafer Marissa J,
Roos Carolyn M,
Miller Jordan D,
Robertson Neil,
Mann Jelena,
Adams Peter D,
Tchkonia Tamara,
Kirkland James L,
MialetPerez Jeanne,
Richardson Gavin D,
Passos João F
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2018100492
Subject(s) - telomere , senescence , biology , mitosis , ageing , phenotype , dna damage , microbiology and biotechnology , cancer research , genetics , dna , gene
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.