Senescent cells most likely contribute meaningfully to all age-related conditions. Cells become senescent in response to damage, a toxic environment, the signals of other senescent cells, but most often because they reach the Hayflick limit on replication. Cellular senescence is useful in a number of contexts when senescent cells are present for a short period of time only, such as regeneration from injury and suppression of precancerous cells. Senescent cells secrete a mix of pro-growth, pro-inflammatory signals that attract the immune system to help to address these issues. The problem starts when senescent cells linger over time and steadily increase in number with advancing age. Their presence becomes disruptive to tissue structure and function.
In today’s open access paper, the authors discuss the role of senescent cells in the vasculature in the development of cardiovascular disease. Interestingly, there has been little focus on cardiovascular disease to date on the part of the few groups involved in running clinical trials for first generation senolytic drugs, treatments capable of selectively destroying senescent cells. In fairness, when the possible set of age-related conditions to treat is “all of them,” some conditions are going to be left behind. There are only so many researchers, only so much funding. But still, cardiovascular disease is the largest cause of human mortality. There is something to be said for starting at the top and working down.
Targeting vascular senescence in cardiovascular disease with aging
This review aimed to provide a brief summary of the effects of aging on cardiovascular disease through the accumulation of senescence, highlighting the crucial involvement of vascular cells in the progression of atherosclerosis and other cardiovascular diseases (CVDs). We also sought to describe the potential of senolytics to improve vascular function and reduce CVD in aging. Endothelial dysfunction occurs with aging and promotes reductions in nitric oxide (NO), increases in reactive oxygen species (ROS), a proinflammatory phenotype, and is associated with an increase in senescent cell accumulation. Understanding how endothelial cell (EC) senescence influences endothelial dysfunction, atherosclerosis, and CVD is important in the identification/design of novel effective therapeutics.
EC senescence is recognized as a contributing factor to endothelial dysfunction and is a major step in the development of atherosclerosis and other CVDs. Evidence suggests that genetic or pharmacological elimination of senescence, specifically in ECs, can attenuate vascular dysfunction and disease in aging through a reduction in the milieu of senescence-associated secretory phenotype (SASP) factors present in senescence. These findings have also improved our understanding of the endothelium’s response to aging and how to combat endothelial dysfunction in this setting. Specifically, targeting endothelial cell senescence appears to be a promising strategy for maintaining endothelial functions and improving vascular health.
Preclinical evidence has shown the potential of senolytics for the treatment and prevention of CVD, leading to the investigation of senolytic therapy in the clinical setting. In a preliminary clinical trial investigating the effectiveness of senolytics, a treatment regimen involving a 3-day administration of dasatinib and quecertin (D&Q) per week for 3 weeks was implemented. This study was conducted on 14 patients with idiopathic pulmonary fibrosis and demonstrated high retention and completion rates, indicating the safety of this treatment. Although there were no significant improvements in pulmonary function, treatment with D&Q led to notable improvements in physical function, as evidenced by increases in 6-min walk distance and 4-min gait speed. Moreover, correlations were observed between enhanced physical function and a reduction in SASP factors.
Additionally, preliminary data from a phase 1 clinical trial involving patients with diabetic kidney disease revealed that senolytic therapy with D&Q reduced senescence burden in both adipose and epidermis tissue. This reduction was associated with a decrease in circulating cytokines and matrix metalloproteinases. In a 12-week pilot study of D&Q treatment on individuals with early-stage Alzheimer’s disease (AD), there was no significant difference between neuroimaging endpoints and cognitive function. However, results indicated a reduction in cytokine and chemokine levels associated with senescence as well as a trending increase in Aβ42, a biomarker that is inversely related to Alzheimer’s disease diagnosis. These studies show promise for the therapeutic potential of senolytic therapy in eliminating senescence, relieving SASP accumulation, and reducing inflammation, although more compounds with appropriate safety, tolerability, and feasibility need to be developed and investigated. Moreover, clinical trials using senolytic therapy in the context of atherosclerosis and cardiovascular disease should be conducted.
Currently, there is not enough research on the use and treatment of senolytic therapy in cardiovascular diseases in the clinical setting. It is unclear if senescent cell clearance, either systemically or in a cell-specific manner, will impact the cardiovascular system, specifically on health span in general. Furthermore, the long-term effects of senescent cell elimination, both systemic and tissue-specific, are not well known. More research must be conducted to answer these questions. While short-term clearance of senescent endothelial and vascular smooth muscle cells improved cardiovascular function and atherosclerosis in preclinical models, further studies are necessary to ensure that the elimination of this cell population has no adverse effects on systemic function, both long-term and short-term. Nevertheless, the potential of senolytics to transform age-related cardiovascular diseases and improve health span is an exciting frontier.
