| Summary: | Dietary restriction (DR), the reduction in food intake that falls short of starvation, has been shown to be the most robust and reproducible intervention to extend lifespan in diverse organisms ranging from yeast to mammals, including the fruit fly Drosophila. Despite over 70 years of research, primarily on rodents, the mechanisms by which DR extend lifespan in any organism are poorly understood, partially due to the variation in how DR is defined and applied between laboratories. Lifespan extension by DR commonly trade-offs with reduced fecundity, leading to evolutionary-based theories predicting that DR elicits an evolved response to food shortage in nature, through reallocation of resources away from reproduction and towards somatic maintenance, hence increasing the chance of survival until food supply becomes more abundant. In Drosophila, DR is typically implemented by dilution of sucrose and yeast in an agar-based medium, with yeast being the key component regulating lifespan. Firstly, this thesis presents an investigation of the response of the model organism Drosophila to different DR diets and protocols, thereby creating one standardized and optimized DR diet for use. Secondly, using the optimized diet, this project investigates the role of specific nutrients mediating the effects of DR and the potential pathways controlling these effects. Essential amino acids were shown to directly regulate the trade-off between high fecundity and reduced lifespan observed with full feeding. However, methionine addition alone was necessary and sufficient to increase fecundity to levels seen with full feeding, without reducing lifespan, demonstrating that reallocation of nutrients cannot explain the DR responses. The results of this thesis highlight the importance for a standard DR protocol and suggest that in other organisms, including mammals, the beneficial effects of DR may be achieved without impairing fertility by using a suitable balance of nutrients in the diet.
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