My previous post dove into some of the mechanisms underlying cardiovascular disease, including metabolic disturbance, vasculature stiffening, endothelial dysfunction, poor mitochondrial performance, oxidative stress, and chronic inflammation. Age-associated senescence is another contributor to low-grade inflammation. Senescent cells secrete a variety of injurious and immune-activating compounds which characterize their pro-inflammatory, senescence-associated secretory phenotype (SASP). Transitory cardiomyocyte and myofibroblast senescence following myocardial infarction and consequent cell damage can mitigate excess fibrosis and scar formation brought on by overzealous extracellular matrix remodeling. However, as senescent cell load accumulates with age, the burden of their inflammatory nature negatively impacts the tissues around them. Senescent cells remain metabolically active but exist in a state of limbo, permanently removed from the cell cycle. These sick cells are irreparable, unable to participate in tissue regeneration yet resistant to apoptosis.
Senotherapeutics are a class of drugs designed to promote the clearance of such parasitic cells. Senolytics selectively attack senescent cell anti-apoptotic proteins to assist with senescent cell removal. Senomorphics, on the other hand, are designed to recognize and target the senescence-associated secretory phenotype, thereby attenuating senescent cell build-up. The primary senolytic agents identified to date are Dasatinib, quercetin, Navitoclax, and fisetin. Administered in a pulsed manner, these compounds have been shown to cull senescent cells and reduce tissue and physiological impairment.
In rodent models, senolytics alleviated hypertrophy and fibrosis in the myocardium, and enhanced cardiomyocyte turnover and endothelial health to restore cardiac function. The heart displayed improved ability to remodel and regenerate following cardiac injury when senolytics were incorporated. Clinical studies have also demonstrated promise in the amelioration of chronic conditions including idiopathic pulmonary fibrosis, diabetic kidney disease, and Alzheimer’s disease. Patients consistently experienced elevations in functional capacity as well as diminished senescence-related cytokine production and senescent-cell load. However, current evidence of senolytic efficacy in cardiovascular disease is lacking. Larger, placebo-controlled trials are needed to investigate senolytic use in additional disease states, optimal dosing strategies, and long-term outcomes.
Ellison-Hughes GM, Torella D. Targets of senescence in cardiac muscle: insights for regenerative treatments in the aged heart. Expert Opin Ther Targets. 2026;30(5):429-436. doi:10.1080/14728222.2026.2671690