Length-independent telomere damage drives cardiomyocyte senescence
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.
Subject Area
- Biochemistry (11752)
- Bioengineering (8752)
- Bioinformatics (29200)
- Biophysics (14974)
- Cancer Biology (12096)
- Cell Biology (17411)
- Clinical Trials (138)
- Developmental Biology (9421)
- Ecology (14182)
- Epidemiology (2067)
- Evolutionary Biology (18308)
- Genetics (12245)
- Genomics (16803)
- Immunology (11869)
- Microbiology (28097)
- Molecular Biology (11594)
- Neuroscience (60969)
- Paleontology (451)
- Pathology (1871)
- Pharmacology and Toxicology (3238)
- Physiology (4959)
- Plant Biology (10427)
- Synthetic Biology (2886)
- Systems Biology (7340)
- Zoology (1651)