Mammalian ageing is defined as a gradual loss of the capacity to maintain tissue homeostasis or to repair tissues after injury/stress. The adult heart is considered a post-mitotic organ, having a low cardiomyocyte turnover rate over the course of human lifespan, which decreases further with ageing. Like other tissues and organs senescent cells accumulate in the heart with ageing and in chronic disease, contributing to pathophysiology and deterioration. Regulation of cell senescence will impact the efficacy of reparative therapies, especially if most patients in need are of advanced age as occurs with heart disease and failure. Targeting cell senescence presents a promising therapeutic target to rejuvenate the heart’s reparative potential.

We and others have shown that eliminating senescent cells using senolytics (Navitoclax, Dasatanib+Quercetin) or genetic (using INK-ATTAC+AP mice) clearance of senescent cells in aged mice alleviated detrimental features of cardiac ageing, including myocardial dysfunction, hypertrophy and fibrosis, and induced cardiac progenitor cell activation and cardiomyocyte renewal.  We also show that D+Q senolytics ameliorate cardiac recovery and remodelling after injury in adult and aged mice.

A key feature of senescent cells is that they produce and secrete pro-inflammatory factors, termed the senescence-associated secretory phenotype (SASP). Long-term persistence of senescent cells and their SASP disrupts tissue structure and function with deleterious paracrine/autocrine and systemic effects. We show that the SASP decreases survival and proliferation of human cardiac progenitor cells, iPSC-derived cardiomyocytes and endothelial cells. Moreover, endothelial cells show impaired tube formation and migration. D+Q senolytics, by eliminating senescent cells and therefore abrogating the SASP, improves human CPC, iPSC-derived cardiomyocyte survival and proliferation, and endothelial cell survival, migration and tube formation.

In conclusion, targeting cell senescence using senotherapeutics can rejuvenate the reparative potential of the heart.