Longevity-associated metabolites as mediators of organ protection

长寿研究导致确定了越来越多的延长寿命的干预措施。关于对人类的转化，这些干预措施提高细胞应激抵抗力的潜力是主要关注点，并且已被证明可以有效保护免受急性肾损伤（阿基）。我们实验室的工作为当前的知识做出了贡献，包括秀丽隐杆线虫（C。elegans）和小鼠模型进行临床试验。简而言之，我们能够证明，（1）延长线虫寿命的干预措施是预防小鼠阿基的有效策略，（2）这些干预措施的代谢结果是保护能力的核心，（3）线粒体是中心靶点，以提供第一个证据证明（4）这些方案在临床试验中是可行的。虽然我们的研究重点是肾脏作为模型器官，但干预措施的保护潜力预计也适用于其他靶组织。此外，由此产生的策略可能会带来细胞再生效果，并在长期应用时预防衰老相关的衰退。然而，在临床环境中充分发挥潜力的工作显然滞后。因此，需要有针对性的策略来实现成功的翻译。目前，我们正在几项正在进行的临床试验中朝着这种靶向方法发展-检查例如含硫氨基酸（SAA）的限制-以及基于我们先前工作的遗传小鼠模型，比较不同的靶向饮食方案（例如SAA限制，生酮饮食）和药理学干预（例如PHD抑制）。然而，除了传统的饮食干预和考虑简化翻译，药理学策略，包括膳食补充剂是一个重要的目标。在这种情况下，补充延长寿命的饮食中所含的特定成分以及这些方案诱导的代谢物是非常有趣的。在手头的项目中，我们建议（1）使用线虫模型系统地筛选并直接比较这些化合物对寿命的影响，（2）在急性肾损伤小鼠模型中检查作为器官保护介质的最有效候选物，（3）分析这些化合物在接受饮食干预的人类队列中的调节。这个翻译项目的目的是作出重大贡献，对确定最有效的组合治疗进行检查，在临床试验中对肾保护在未来。

Longevity research has led to the identification of a growing number of lifespan-extending interventions. Regarding translation to humans, the potential of these interventions to increase cellular stress resistance is of major interest and has been shown to effectively protect from acute kidney injury (AKI). Work from our lab has contributed to the current knowledge including studies from basic research in Caenorhabditis elegans (C. elegans) and mouse models to clinical trials. Briefly, we were able to show, that (1) interventions extending lifespan in the nematode are potent strategies to prevent AKI in mice, that (2) metabolic consequences of these interventions are central to the protective capacity and (3) mitochondria are a central target, to provide first evidence that (4) these protocols are feasible in clinical trials. Whilst our research focusses on the kidney as a model organ, the protective potential of the interventions is expected to be applicable to other target tissues. Besides, the resulting strategies are likely to come with cellular rejuvenation effects and prevention of aging-associated decline when applied in the longer term. However, exploitation of the full potential in the clinical setting is clearly lagging behind. Consequently, targeted strategies will be required to achieve successful translation. Currently, we are moving towards such targeted approaches in several ongoing clinical trials - examining e.g. restriction of sulfur-containing amino acids (SAA)- as well as genetic mouse models based on our previous work, comparison of different targeted dietary regimens (e.g. SAA restriction, ketogenic diets) and pharmacological interventions (e.g. PHD inhibition). However, beyond classical dietary interventions and considering simplified translation, pharmacological strategies including dietary supplements are an important goal. In this context, supplementation of specific components contained in lifespan-extending diets as well as the metabolites induced by these regimens are highly interesting. In the project at hand, we propose to (1) systematically screen and directly compare such compounds regarding their impact on lifespan using the nematode model, (2) examine the most potent candidates as mediators of organ protection in a mouse model of acute kidney injury and (3) analyze the modulation of these compounds in human cohorts undergoing dietary interventions. This translational project is designed to make a major contribution towards the identification of the most potent combinatorial treatment to be examined in clinical trials on nephroprotection in the future.