Senolytic therapies for cardiovascular aging: tackling fibrosis and metabolic dysfunction.

Abstract

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality, with aging as a critical risk factor. Cellular senescence, marked by irreversible cell cycle arrest and a pro-inflammatory secretory phenotype, drives age-related cardiovascular pathologies, including vascular dysfunction, atherosclerosis, cardiac fibrosis, and metabolic disturbances. Senolytics-agents that selectively eliminate senescent cells-represent a promising therapeutic strategy. This review explores the role of senescence in CVD and evaluates senolytics potential to improve vascular function, reduce fibrosis, and address CVD-related metabolic and immune dysfunctions. Preclinical studies have shown promising results in improving heart function, particularly in the treatment of heart failure, in post-myocardial infarction recovery, and cardiac transplantation. The interplay between senescence and immunosenescence in CVD is also examined, highlighting the potential of senolytics to rejuvenate immune responses and attenuate chronic inflammation. Furthermore, the review discusses the role of senolytics in addressing metabolic syndrome, a significant contributor to CVD, by alleviating systemic inflammation and insulin resistance. While clinical data remain limited, early-phase trials and strong preclinical evidence provide a compelling rationale for further investigating senolytics in cardiovascular contexts. In this light, the review concludes by emphasizing the challenges and the need for extended preclinical and clinical studies to establish the efficacy, safety, dose, and long-term effects of senolytics and to exploit them as a transformative approach in cardiovascular medicine.