Strategies for combating senescence in endothelial cells

Diseases of the cardiovascular system are the most common cause of morbidity and mortality in developed countries. The numerous clinical consequences of these pathologies range from stroke and myocardial infarction to kidney failure and peripheral vascular diseases. Endothelial cells, forming the inner lining of blood vessels and thus the interface between blood and tissue, are responsible for the exchange of oxygen, nutrients, and waste products, and also participate in the regulation of the vascular tone or the formation of new blood vessels. With increasing age or the induction by chronic stress such as oxidation, inflammation, or elevated blood sugar levels, endothelial cells can adopt a "senescent phenotype". This state is characterized by the loss of capacity for cell division, partial loss of endothelial cell function, and by the sustained secretion of pro-inflammatory proteins. While the notion that senescent cells crucially contribute to the pathology of many age-related pathologies has found validation recently, the sequence of events whereby cells lose their ability to propagate and become a source of chronic inflammation has not been sufficiently clarified. Hence, since endothelial senescence is associated with cardiovascular disease, the number one killer in the industrialized world, there is great urgency in exposing the pathways taken by these cells following their exposure to stress on their road to becoming senescent and an inflammatory burden. Within this project, we aim to study the process of how endothelial cells become senescent. To this end, we will use an unbiased proteomic approach, gene-array analysis, and microscopy techniques. Upon the exposure of endothelial cells to several senescence-inducing stresses, including oxidative stress, chronic exposure to inflammatory mediators, or extensive cell division, we propose to distill the common processes that are responsible for establishing this process. This will result in the compilation of a set of parameters that could be used for assessing the aforementioned state of endothelial cells. These data should contribute to the further development of diagnostic approaches for detecting vascular senescence. In the second part of the project, we will investigate a panel of pre-selected substances for their ability to eliminate selectively senescent endothelial cells, while sparing non-senescent ones. Those anti-inflammatory substances that we intend to study will include plant-derived substances as well as synthetic compounds that have been previously studied by us and others. As shown recently, such a senolytic approach may carry great potential for treating age-related diseases, in particular cardiovascular diseases. Altogether, this project will not only expand our current knowledge on the mechanisms of how endothelial cells become senescent, but it may also contribute to outlining ways of pharmacologically thwarting endothelial senescence.

The "Strategies to combat senescence in endothelial cells" project was a comprehensive study of the aging process of endothelial cells, which play a central role in cardiovascular health. Cellular senescence, characterized by a permanent loss of replication potential, can be triggered by various stressors such as DNA damage, oxidative stress, and mitochondrial dysfunction. By releasing inflammatory factors, senescent cells contribute to chronic inflammation, a key factor in cardiovascular disease. Recognizing the close connection between endothelial cell senescence and these health conditions, our project aimed to decipher the processes underlying cellular aging in response to stress and, more importantly, to pursue strategies for targeted interventions. Our first goal was to use advanced proteomic techniques, gene array analysis, and state-of-the-art microscopy to gain insights into the unique properties of aging endothelial cells. These findings have the potential to identify targets for selective drugs to target such cells. The second aim of this project was to test candidate substances for their suitability to selectively eliminate senescent cells and leave healthy cells unaffected. That elimination of senescent cells can improve overall health and promote healthy aging has already been convincingly demonstrated in the mouse. In this second phase of the project, our focus therefore shifted to identifying such selective substances. We have investigated a number of anti-inflammatory substances, including both natural and synthetic compounds, that have shown promise as potential treatments for age-related diseases, particularly those related to cardiovascular health. During these studies, we discovered that statins, commonly prescribed lipid-lowering medications for patients at risk of cardiovascular events, possess senolytic properties. Through experiments with two different models of senescence in human vascular endothelial cells (HUVECs), we found that statins can effectively and selectively eliminate senescent cells, albeit in a narrow concentration range. In our experiments, statins induced the detachment of senescent cells, ultimately leading to apoptosis-like cell death. This discovery furthermore fosters the speculation that the repeatedly described cardiovascular benefits of statins may be potentially related to their senolytic effect. Further research is needed to investigate the potential of high-dose statin treatment for a few days as a potential senolytic therapy that offers new hope for age-related and cardiovascular diseases.