Post-mitotic cardiomyocyte senescence redefines cardiac ageing

For decades, cellular senescence was regarded as a hallmark of proliferative cells. First described as an irreversible cell-cycle arrest that limits the propagation of damaged cells, senescence was widely viewed as a potent tumour-suppressive mechanism. Senescent cells also emerged as key drivers of chronic diseases, which fuelled intense efforts to develop senolytic drugs (which selectively eliminate senescent cells) and senomorphic therapies (which modulate the senescence-associated secretory phenotype (SASP)) for age-related disorders. However, because cardiomyocytes are post-mitotic cells, they were largely considered exempt from senescence biology. Therefore, whether terminally differentiated cells could also undergo senescence remained largely unexplored.

This paradigm shifted with the 2019 landmark study by Anderson and colleagues, who showed that post-mitotic cardiomyocytes progressively acquire a senescent phenotype with age. Rather than defining senescence by proliferative arrest, the investigators established that persistent cellular stress triggers a senescence program even in differentiated cells. By demonstrating that senescence can develop independently of cell-cycle arrest, the investigators expanded the concept of cellular senescence beyond proliferative tissues and redefined cardiomyocytes as active drivers of cardiac ageing. Most importantly, the study established that senescent cardiomyocytes are not merely passive markers of ageing. Instead, these cells actively remodel the myocardial microenvironment through a non-canonical SASP enriched in pro-fibrotic and pro-hypertrophic mediators. Despite representing only a small fraction of the cardiomyocyte population, senescent cardiomyocytes were shown to promote myocardial fibrosis and cardiomyocyte hypertrophy in mice, suggesting that a limited number of dysfunctional cells is sufficient to orchestrate tissue-wide remodelling. This concept fundamentally changed how researchers viewed the ageing myocardium: not as a tissue that simply accumulates damaged cardiomyocytes, but as one in which stressed cardiomyocytes actively instruct pathological remodelling.

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