Therapeutic Potential of Senolytics in Cardiovascular Disease

Abstract

Ageing is the biggest risk factor for impaired cardiovascular health, with cardiovascular disease being the leading cause of death in 40% of individuals over 65 years old. Ageing is associated with both an increased prevalence of cardiovascular disease including heart failure, coronary artery disease, and myocardial infarction. Furthermore, ageing is associated with a poorer prognosis to these diseases. Genetic models allowing the elimination of senescent cells revealed that an accumulation of senescence contributes to the pathophysiology of cardiovascular ageing and promotes the progression of cardiovascular disease through the expression of a proinflammatory and profibrotic senescence-associated secretory phenotype. These studies have resulted in an effort to identify pharmacological therapeutics that enable the specific elimination of senescent cells through apoptosis induction. These senescent cell apoptosis-inducing compounds are termed senolytics and their potential to ameliorate age-associated cardiovascular disease is the focus of this review.

Keywords: Atherosclerosis; Cardiovascular; Inflammation; Remodelling; Senescence; Senolytic.

Fig. 1

Cellular senescence and cardiovascular disease. Senescence is induced in multiple cardiovascular lineages and immune cell populations in response to a variety of stimuli including telomere attrition, telomere damage and genomic DNA damage, which leads to activation of the DDR. If the DDR is persistent, activation of tumour suppressor genes p53, p21, p16^Ink4A and p19^Arf establish cell cycle arrest and coordinate the senescence program, which can include cellular hypertrophy and expression of the SASP. Senescent cells up-regulated pro-survival pathways such as Bcl-2 and Bcl-XL that protect them from their own pro-apoptotic SASP. Cellular senescence and its associated SASP contribute to CVD including promoting inflammation, fibrosis, endothelial dysfunction and stenosis and progression of atherosclerosis. The SASP can also drive paracrine senescence in surrounding cells via the bystander effect which may further contribute to CVD pathophysiology

Fig. 2

Therapeutic potential of senolytics in cardiovascular disease