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, Joao Passos

Research output: Contribution to journalArticle

19 Citations (Scopus)

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

Fingerprint

Telomere
Cardiac Myocytes
Aging of materials
Telomere Shortening
Phenotype
Cell Aging
Tissue
Cell Division
Hypertrophy
DNA Damage
Fibrosis
Cardiovascular Diseases
Pharmacology
Cells
DNA

Keywords

  • ageing
  • cardiomyocytes
  • senescence
  • senolytics
  • telomeres

ASJC Scopus subject areas

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

Cite this

Anderson, R., Lagnado, A., Maggiorani, D., Walaszczyk, A., Dookun, E., Chapman, J., ... Passos, J. (2019). Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO Journal, 38(5), [e100492]. https://doi.org/10.15252/embj.2018100492

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

In: EMBO Journal, Vol. 38, No. 5, e100492, 01.03.2019.

Research output: Contribution to journalArticle

Anderson, R, Lagnado, A, Maggiorani, D, Walaszczyk, A, Dookun, E, Chapman, J, Birch, J, Salmonowicz, H, Ogrodnik, M, Jurk, D, Proctor, C, Correia-Melo, C, Victorelli, S, Fielder, E, Berlinguer-Palmini, R, Owens, A, Greaves, LC, Kolsky, KL, Parini, A, Douin-Echinard, V, LeBrasseur, NK, Arthur, HM, Tual-Chalot, S, Schafer, MJ, Roos, CM, Miller, JD, Robertson, N, Mann, J, Adams, PD, Tchkonia, T, Kirkland, JL, Mialet-Perez, J, Richardson, GD & Passos, J 2019, 'Length-independent telomere damage drives post-mitotic cardiomyocyte senescence', EMBO Journal, vol. 38, no. 5, e100492. https://doi.org/10.15252/embj.2018100492
Anderson R, Lagnado A, Maggiorani D, Walaszczyk A, Dookun E, Chapman J et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO Journal. 2019 Mar 1;38(5). e100492. https://doi.org/10.15252/embj.2018100492
Anderson, Rhys ; Lagnado, Anthony ; Maggiorani, Damien ; Walaszczyk, Anna ; Dookun, Emily ; Chapman, James ; Birch, Jodie ; Salmonowicz, Hanna ; Ogrodnik, Mikolaj ; Jurk, Diana ; Proctor, Carole ; Correia-Melo, Clara ; Victorelli, Stella ; Fielder, Edward ; Berlinguer-Palmini, Rolando ; Owens, Andrew ; Greaves, Laura C. ; Kolsky, Kathy L. ; Parini, Angelo ; Douin-Echinard, Victorine ; LeBrasseur, Nathan K ; Arthur, Helen M. ; Tual-Chalot, Simon ; Schafer, Marissa J. ; Roos, Carolyn M. ; Miller, Jordan D ; Robertson, Neil ; Mann, Jelena ; Adams, Peter D. ; Tchkonia, Tamara ; Kirkland, James L ; Mialet-Perez, Jeanne ; Richardson, Gavin D. ; Passos, Joao. / Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. In: EMBO Journal. 2019 ; Vol. 38, No. 5.
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