Senolysis in kidney disease: Therapeutic potential and risks

在过去的十年中，细胞衰老（一种细胞命运程序）对衰老以及几种疾病过程的重要性已经得到证明。衰老细胞被锁定在一种非分裂状态，在这种状态下，它们不再能够维持组织的完整性，并且通过创造促炎微环境对正常器官的维持有害。事实上，针对衰老细胞的新策略已经在几个器官系统中显示出对抗功能衰退、慢性炎症和年龄依赖性修复能力丧失的希望。随着年龄的增长，衰老细胞在肾脏中积累，并且作为肾脏疾病的一部分独立于年龄而发生，使其成为治疗方法的重要靶点。我们的目标是在我们建立的细胞和动物模型中评估已知的抗衰老药物的有效性和安全性。我们将验证选择性杀死衰老细胞可以用来改善与年龄相关的肾功能丧失和抵消加速衰老表型的假设。为此，我们将在Aim 1中评估减少肾脏衰老细胞负担的最有效方法。在体外选择最有前途的抗衰老化合物的基础上，我们将进一步评估这些药物的短期应用是否会改善急性肾损伤后的结果，无论是在按时间顺序衰老的小鼠，还是在经历了促衰老肾应激的年轻小鼠中。此外，我们将启动长期药物应用，研究其对肾脏年代性衰老变化的影响。目的2解决了当边缘供肾被使用时，围手术期应用这些抗衰老化合物是否会改善移植结果的问题。对于这种方法，我们将首先在体外测试不同的抗衰老药物在灌注条件下消除衰老细胞的潜力，然后将进一步评估在同种异体和同种异体环境下预处理器官的结果。在转化方法中，我们将使用移植的肾脏来看看我们的发现是否可以转化到人类环境中。本研究的总体目标是双重的：首先，评估“衰老溶解”作为一种新方法来改善患病的原生肾脏和肾移植的结果；其次，为衰老细胞的存在与肾功能下降之间的因果关系提供证据。

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.