Length-independent telomere damage drives cardiomyocyte senescence

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, W. A.; Greaves, L.; Kolsky, K.; Parini, A.; Douin-Echinard, V.; LeBrasseur, N.; Arthur, H.; Tual-Chalot, S.; Schafer, M.; Roos, C.; Miller, J.; Robertson, N.; Mann, J.; Adams, P. D.; Tchkonia, T.; Kirkland, J. L.; Mialet-Perez, J.; Richardson, G. D.; Passos, J. F.

doi:10.1101/394809

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bioRxiv · 10.1101/394809

Length-independent telomere damage drives cardiomyocyte senescence

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Abstract

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, p21CIP and p16INK4a 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 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.

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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, W. A., Greaves, L., Kolsky, K., Parini, A., Douin-Echinard, V., LeBrasseur, N., Arthur, H., Tual-Chalot, S., Schafer, M., Roos, C., Miller, J., Robertson, N., Mann, J., Adams, P. D., Tchkonia, T., Kirkland, J. L., Mialet-Perez, J., Richardson, G. D., Passos, J. F.. 2018-08-17. Length-independent telomere damage drives cardiomyocyte senescence. https://doi.org/10.1101/394809

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