Amazentis: Evaluation of nutraceuticals against age-related diseases
i. Objective of research: To test natural compounds on ageing and age-related diseases models available amongst the HealthAge network.
ii. Current state of the art: Mitochondrion is a central organelle that can drive both cellular life, i.e. by producing energy in the respiratory chain, and death, i.e. by initiating apoptosis. Dysfunctional mitochondria can be specifically targeted for elimination by autophagy, a process that has been termed mitophagy. During ageing, there is a progressive decline in the cell capacity to eliminate its dysfunctional elements by autophagy. Therefore, restoring levels of autophagy and mitophagy and boosting mitochondrial function in the elderly represents a promising approach to halt the development of age related disorders. Amazentis has identified Urolithin A (UA) as the first inducer of mitophagy. UA extends lifespan and fitness of the worm C. elegans, while in rodents it is bioavailable in muscle and improves running capacity in both young rats and old mice fed with an optimal chow diet or under conditions of metabolic challenge. Also published recently was the safety profile of directly consumed UA in preclinical models and demonstrated that subchronic exposure of rats did not show any specific toxic mechanisms. This year, Amazentis announced the completion of a Phase 1 trial in elderly, which again showed a very safe profile of UA in this population, making it a strong candidate for age-associated conditions.
iii. Research methodology and approach: In the current project, Amazentis will first characterize the anti-ageing effects of its lead compound UA in the relevant pre-clinical models available amongst the HealthAge network. The aims of this part of the project will be to (1) understand the relationship between mitophagy and other mechanisms of ageing, (2) identify novel applications for UA. In parallel, Amazentis will carry out detailed characterization a series of naturally derived ingredients in relevant pre-clinical models, in order to select the best ones for further development toward the clinic. The first model of choice will be C. elegans strains, a particularly useful tool to measure the impact of the compounds on lifespan extension and age-related phenotypes. In addition, mutant strains that are model for age-related disorders (e.g. neurodegenerative disorders) or worms that carry mutations in genes of the Nucleotide Excision Repair pathway will be tested. The best compounds and conditions identified in worms will be further tested in vitro and in rodent models.
iv. Originality and innovative aspects of the ESR project: We propose to (1) use the first described inducer of mitophagy to understand the relationship between mitochondrion and other mechanisms of ageing (2) identify other natural compounds with potent anti-ageing effects.
v. Integration of the ESR project to the overall research programme: Our ESR will test the impact of specialized nutraceuticals on mitophagy (with the Auwerx group), on DNA damage responses (with the Schumacher group) and on NER progeria (with the Garinis group).