Longevity-associated metabolites as mediators of organ protection

• Applicant: Professor Dr. Roman-Ulrich Müller
• Subject Area: Nephrology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 493103359

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.

• DFG Programme: Research Grants