Length‐independent telomere damage drives post‐mitotic cardiomyocyte senescence

Rhys Anderson (1, 2) , Anthony Lagnado (1, 2) , Damien Maggiorani (3) , Anna Walaszczyk (4) , Emily Dookun (2) , James Chapman (1, 2) , Jodie Birch (1, 2) , Hanna Salmonowicz (1, 2) , Mikolaj Ogrodnik (1, 2) , Diana Jurk (1, 2) , Carole Proctor (1, 2) , Clara Correia-Melo (1, 2) , Stella Victorelli (1, 2) , Edward Fielder (1, 2) , Rolando Berlinguer-Palmini (5) , Andrew Owens (4) , Laura C Greaves (6) , Kathy L Kolsky (7) , Angelo Parini (3) , Victorine Douin-Echinard (8) , Nathan K Lebrasseur (7) , Helen M Arthur (4) , Simon Tual-Chalot (4) , Marissa J Schafer (7) , Carolyn M Roos (7) , Jordan Miller (7) , Neil Robertson (9) , Jelena Mann (9) , Peter D Adams (9) , Tamara Tchkonia (7) , James L Kirkland (7) , Jeanne Mialet-Perez (8) , Gavin D Richardson (4) , João F Passos (1, 2)

1 Institute for Ageing - Ageing Research Laboratories [Newcastle upon Tyne, UK]
2 Institute for Cell and Molecular Biosciences
3 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
4 Institute for Genetic Medicine - Cardiovascular Research Centre [Newcastle upon Tyne, UK]
5 The Bio-Imaging Unit [Newcastle upon Tyne, UK]
6 Institute of Genetic Medicine - Wellcome Trust Centre for Mitochondrial Research [Newcastle upon Tyne, UK]
7 Robert and Arlene Kogod Center on Aging [Rochester, MN, USA]
8 I2MR - Institut de médecine moléculaire de Rangueil
9 CR-UK Beatson Institute - Institute of Cancer Sciences [Glasgow, UK]

Ageing is the biggest risk factor for cardiovascular health and is associated with increased incidence of 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 if 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. Pharmacological or genetic clearance of senescent cells in mice alleviates myocardial hypertrophy and fibrosis, detrimental features 2 of cardiac ageing, and promotes cardiomyocyte regeneration. Our data describes a mechanism by which senescence can occur and contribute to ageing in post-mitotic tissues.

Mots clés: senescence; senolytics; ageing; telomeres; cardiomyocytes; telomeres Subject Categories Ageing; DNA Replication; Repair & Recombination; Metabolism

Domaines: Sciences du Vivant [q-bio]; Biologie cellulaire

Rhys Anderson, Anthony Lagnado, Damien Maggiorani, Anna Walaszczyk, Emily Dookun, et al.. Length‐independent telomere damage drives post‐mitotic cardiomyocyte senescence. EMBO Journal, 2019, 38 (5), pp.e100492. ⟨10.15252/embj.2018100492⟩. ⟨inserm-02445949⟩