Senolysis in kidney disease: Therapeutic potential and risks

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The importance of cellular senescence, a cell fate program, for aging, but also several disease processes has been shown over the past decade. Senescent cells are locked in a non-dividing state, in which they are no longer able to maintain tissue integrity and are harmful for normal organ maintenance by creation of a pro-inflammatory microenvironment. In fact, novel strategies in targeting senescent cells have shown promise in several organ systems to counteract functional decline, chronic inflammation and age-dependent loss of repair capacity. Senescent cells accumulate in the kidney with advancing age and also occur independent of age as a part of renal diseases making them an important target for therapeutic approaches.Our objective is to evaluate known senolytic drugs for their efficacy and safety in our established cellular and animal models. We will test the hypothesis that selective killing of senescent cells can be utilized to improve age-associated loss of kidney function and to counteract the accelerated aging phenotype. For this purpose we will evaluate in Aim 1 the most effective way to decrease the burden of senescent cells in the kidney. Based on in vitro selection of the most promising senolytic compounds, we will then further evaluate whether short-term application of those drugs will improve outcome after acute kidney injury in chronologically aged mice as well as in young mice, which have undergone pro-senescent kidney stress. In addition, we will initiate long-term drug application to study its effect on chronological aging changes in the kidney. Aim 2 addresses the question whether peri-operative application of such senolytic compounds leads to an improvement in transplantation outcome when marginal donor kidneys are utilized. For this approach, we will first test different senolytic drugs ex vivo for their potential to eliminate senescent cells under perfusion conditions and will then further evaluate the outcome of pre-treated organs in isogeneic and allogeneic settings. In a translational approach, we are going to use explanted kidneys to see whether our findings can be translated into the human setting.The overall goal of this study is twofold: firstly, to evaluate ‘senolysis’ as a novel approach for improving the outcome of diseased native kidneys and of renal transplants; and secondly, to provide evidence for the causal relationship between the presence of senescent cells and renal functional decline.