Scientists in the Partridge lab are using a pharmacological approach to delay ageing, using the fruit fly as a model organism.

It has been known for over two decades now that, remarkably, a mutation in a single gene is sufficient to prolong lifespan and ameliorate health in model organisms, such as yeast, worms, flies and mice. The genes involved belong to cellular nutrient-sensing pathways, one of which is called target-of-rapamycin.

In order for humans to benefit from these genetic findings, scientists led by Prof. Dr. Linda Partridge used the fruit fly Drosophila melanogaster to investigate whether drugs acting through this target-of-rapamycin pathway can also have beneficial effects on lifespan, similarly to their genetic mutants.

Rapamycin - a drug discovered in the soil

Rapamycin, the drug investigated, is named after "Rapa Nui", the native translation for the Easter Islands, where the drug was discovered in a soil sample as a bacterial metabolite. Originally, these bacteria secreted rapamycin into the soil in order to stop the growth of competitive fungi, and to absorb as many nutrients as possible themselves.

Anti-ageing effects of rapamycin in flies

Interestingly, flies fed on this drug lived longer than the controls. The target-of-rapamycin pathway plays many important roles, so the scientists needed to establish which specific mechanism was accountable for the longevity effect. The target-of-rapamycin pathway promotes cell growth when nutrients are abundant, but when nutrients become scarce (or when this pathway is inhibited by rapamycin), then cells stop the energetically costly synthesis of proteins and instead start degrading ("recycling") a portion of themselves in order to survive during the stressful period. This process of cellular self-degradation is called autophagy. Interestingly, this study demonstrated that autophagy is essential to achieve the beneficial effects of rapamycin. Another protein essential for the anti-ageing effects of rapamycin is called S6K, and it was demonstrated previously by Prof. Dr. Partridge and Prof. Dr. Dominic Withers that mice carrying a mutation in this gene live longer.

Why research with flies can be applied to mammals

Since flies have relatively short lifespan, scientists were able to uncover the mechanism by which rapamycin slows ageing. Because the target-of-rapamycin pathway is conserved in evolution, this research with flies is very relevant and can be applied to mammals. Indeed, rapamycin is also the first drug shown to extend lifespan in mice. It is also given to humans, not yet in the context of ageing, but as an immunosuppressant and an anti-cancer drug.

Ageing is a topic of great social and economic importance, and many efforts are focussed on understanding and treating the ageing process. According to this study, the autophagy process and the S6K protein are promising targets for drug interventions to improve health and delay disease in the elderly.

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