期刊
EMBO JOURNAL
卷 38, 期 5, 页码 -出版社
WILEY
DOI: 10.15252/embj.2018100492
关键词
ageing; cardiomyocytes; senescence; senolytics; telomeres
资金
- BBSRC [BB/H022384/1, BB/K017314/1]
- NIH [AG013925]
- Connor Group
- Noaber Foundation
- Region Occitanie, France
- foundation Cariplo [2014-0672]
- MRC-Arthritis Research UK Centre for Integrated research into Musculoskeletal Ageing (CIMA) [MR/K0063121/1]
- BHF [PG/15/85/31744]
- BBSRC [BB/K017314/1, BB/H022384/1] Funding Source: UKRI
- MRC [G0700718, MR/L016354/1] Funding Source: UKRI
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-inducingpathways, p21(CIP) and p16(INK4a), and results in a non-canonicalsenescence-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.
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