The accumulation of senescent cells is a significant contribution to age-related dysfunction and disease. These cells are created constantly in most tissues, and rapidly destroyed by programmed cell death or by the immune system. Unfortunately, in later life the immune system becomes ever less capable and as a result the burden of senescent cells grows. Senescent cells cease replication but secrete a pro-inflammatory mix of signals that, when maintained over the long term, causes structural change and loss of function. This picture may be more complicated in tissues with large non-diving cell populations, such as the brain or the heart, but it seems clear that senescent cells are still a contributing factor in the aging of these organs.
Adult cardiomyocytes in humans are terminally differentiated, i.e., they are post-mitotic/rarely dividing. Thus, telomere shortening/attrition due to repetitive cell division, a major mechanism of senescence in proliferating cells, termed replicative senescence, may not occur in cardiomyocytes. However, length-independent telomere damage, which may be caused by reactive oxygen species (ROS), induces senescence in terminally differentiated cardiomyocytes. Accumulating lines of evidence suggest that cardiomyocytes develop senescence during aging and in response to stresses such as ischemia/reperfusion and myocardial infarction (MI). β-adrenergic receptor stimulation and inflammation may also contribute to cardiomyocyte senescence during aging.
Senescent cardiomyocytes exhibit features of senescence commonly seen in other cell types, including enlarged cell size, DNA damage responses, senescence-associated β-galactosidase (SA-β-gal) activity, and the senescence-associated secretory phenotype (SASP). It should be noted that senescent cells are highly heterogeneous and their properties are dynamically altered. Thus, senescent cardiomyocytes may consist of multiple cell populations with distinct features. Furthermore, senescent cells in the heart can be either beneficial or detrimental depending on the cell types and conditions in which they are induced. Senescence in cardiac fibroblasts and endothelial cells may affect the heart differently from that in cardiomyocytes. Thus, conducting a deeper characterization of the gene expression profile in senescent cardiomyocytes and other cell types in the heart at the single-cell level is important.
There is a great interest in finding strategies to specifically eliminate senescent cells but not non-senescent cells, i.e., senolysis. Growing evidence supports the rationale of senolysis and its anti-aging effects. Since aging is a major risk factor for heart disease, senolysis could represent a promising intervention for the heart with senescent cardiomyocytes. Senolysis can be achieved using senolytic drugs (such as Navitoclax or Dasatinib and Quercetin), pharmacogenetic approaches (including the INK-ATTAC model), and immunogenetic interventions (CAR T cells or senolytic vaccination). Importantly, unlike regenerative and proliferative cells, cardiomyocytes are terminally differentiated. Thus, cardiomyocytes may not be replenished after senolysis. This raises the question of whether senolysis improves cardiac function despite the loss of cardiomyocytes. Although there have been reports suggesting that removal of cardiomyocytes by senolytics has salutary effects, thorough investigation into the mechanisms of cardiomyocyte senescence, especially the mechanisms through which cardiomyocytes develop and maintain the senescent state, is critical to identify or develop strategies for “safe” senolysis.
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