Targeting Cellular Senescence in the Aging Vascular Endothelium
Senescent cells accumulate with age throughout the body. Their secreted signals generate chronic inflammation, change surrounding cellular behavior for the worse, and disrupt tissue maintenance and tissue function. In mice, targeted removal of these cells with senolytic drugs reverses aspects of aging and extends life span. In humans, early clinical trials of these drugs are underway. As noted in this short review paper, there is evidence for cellular senescence to be involved in vascular aging. Senescent cells may contribute to the formation of aneurysms. Senescent macrophages may accelerate the progression of atherosclerosis. Senescent cells promote vascular calcification. And so forth.
Since the initial clinical trials for senolytic drugs are focused on other age-related conditions, it may be some years before there is robust data for vascular aging to show how well the results in mice translate to humans. The first generation senolytics are easily obtained compounds, however, and at least one of these treatments comes with human data to show that it does indeed clear much the same fraction of senescent cells as it does in mice. The self-experimentation and medical tourism communities will be employing these treatments well in advance of further formal publications on their efficacy.
The endothelial cell (EC) monolayer forms the inner cellular lining of all blood vessels forming a critical interface between blood and tissue. Vascular endothelium is involved in physiological functions, which include regulation of blood fluidity, hemostasis and clotting, vascular tone, immune responses, inflammation, angiogenesis, and metabolism. Dysfunction of the endothelium is a major contributor to cardiovascular diseases (CVD) such as stroke, atherosclerosis, hypertension, and diabetes. Chronological aging is the dominant risk factor for CVD, cancer and neurodegenerative diseases and indeed endothelial dysfunctions including arterial stiffening, impaired neovascularization, and loss of tissue-barrier function are evident in age-related disease.
EC dysfunction is a well-accepted hallmark of age-related vascular dysfunction, with the initiation of abnormal inflammatory and thrombotic circuits, arterial stiffening and oxidative stress being central to its biology. Importantly, for our understanding of vascular aging, senescent EC accumulate in aging tissues and contribute to tissue dysfunction.
The field of senolytics, drugs that selectively eliminate senescent cells, is gaining momentum. Dasatinib and Quercetin (D+Q) were some of the first senolytics, which remove senescent cells in vitro and in progeroid mice through targeting of the anti-apoptotic pathways in senescence. Long term oral treatment of D+Q have been shown to improve vascular function in aged or atherosclerotic mice. The D+Q combination has been shown to efficiently reduce senescence cell burden in phase I trials for several senescence-related diseases such as diabetic kidney disease.
Although senescence was initially considered as an all-encompassing phenotypic change, it is now apparent that each cell type exhibits an unique and distinguishing senescence phenotype, one that may also be tissue specific. Hence our understanding of endothelial senescence is still in its infancy. Current findings have indicated that specific depletion of senescent cells reverses age-related changes and prolongs life span. However, caution should be urged as cellular senescence also plays important physiological roles such as in tissue development, wound healing, and tumor inhibition. To achieve optimal success in targeting senescence it will be imperative to have a thorough knowledge of the senescent cell type at play in disease, and their spatiotemporal expression in order to deliver the most appropriate senolytic, senomorphic or drug combination.