The Role of Cellular Senescence and the Senescence-Associated Secretory Phenotype in Vascular Aging: Amelioration by the Natural Senolytic Fisetin

Cardiovascular diseases (CVDs) remain the leading cause of death globally, with advancing age being the primary risk factor for CVD development. Age-related vascular dysfunction, characterized by the stiffening of the large elastic arteries and vascular endothelial dysfunction, represents the primary antecedent to the development of CVDs. As such, understanding the mechanisms that drive age-related vascular dysfunction and establishing effective interventions to improve arterial health are biomedical research priorities. Cellular senescence(definition), a multifactorial stress response, accumulates with advancing age and promotes vascular dysfunction through the production of the senescence-associated secretory phenotype (SASP) which drives chronic inflammation and excess oxidative stress. Senolytics(definition), compounds that selectively eliminate senescent cells, hold promise in reducing excess cellular senescence and the SASP and subsequently improving or preventing age-related vascular dysfunction. The purpose of this dissertation research was to identify promising senolytic interventions to suppress excess cellular senescence and the SASP and enhance vascular function with aging. In a review of the literature, I compiled the putative and established mechanisms by which vascular senescent cells and the SASP may contribute to vascular aging. I collected evidence of the effects of senolytic therapies on vascular health and identified groups that had high cellular senescence and SASP burden and impaired vascular function that might stand to benefit the most from senolytic treatment. In a preclinical intervention study, I found that latelife supplementation with the natural senolytic fisetin enhanced endothelial function and lowered arterial stiffness in old mice. These improvements were mediated by a suppression of excess vascular cell senescence and associated with reduced oxidative stress and favorable remodeling of the arterial wall. In a mechanistic study, I identified aortic endothelial cells to be highly susceptible to becoming senescent in the context of aging and are readily eliminated by fisetin supplementation. Further, I demonstrated that the SASP was an underlying mechanism of agerelated endothelial dysfunction and identified chemokine 12 (CXCL12) as a SASP factor that mediated endothelial dysfunction with aging that could be modulated with senolytic intervention. Collectively, these studies establish cellular senescence and the SASP as causal contributors to the age-related decline in vascular function and demonstrate that senolytic interventions have efficacy in improving or preventing vascular function with aging. Thus, these findings open new avenues for the development of preventative and therapeutic interventions targeting cellular senescence and the SASP to improve cardiovascular health in aging populations.