Using Drosophila as a Model to Identify Novel Geroprotectors

Abstract

Recent advancements in global healthcare have led to increased lifespan with estimations of 2.1 billion people over 60 years of age by 2050. Increased age is the major risk factor of several chronic and age-related diseases. Furthermore, the incidences of multimorbidity where an individual develops multiple chronic conditions also increases with age, reducing quality of life in older people. Urgent preventative measures or therapeutics are needed to combat multimorbidity. Investigations into the underlying mechanisms of ageing has identified several characteristic hallmarks of ageing that describe the systems and processes from which age-related pathologies are thought to develop leading to disease. Recently a group of compounds have been identified that are linked to these ageing hallmarks called geroprotectors – therapeutics that could be used to improve health during ageing and prevent age-related multimorbidity. However, most of these compounds have not yet been tested for effects on ageing or age-related health therefore a rapid screening model is needed. Drosophila are a well-established ageing model but are yet to be fully exploited for drug discovery due to limitations in effective compound delivery. The first aim of this project was to test two potential geroprotectors, carnosine and azithromycin, for their effects on longevity. Neither compound displayed the ability to induce longevity. Azithromycin treatment at high concentrations increased egg laying, however the physiological trade-off of antibiotic treatment was reduction in lifespan. Carnosine administration at a sufficient dose proved problematic, highlighting the limitations of conventional compound administration. The second aim was to develop a new oral drug delivery system for Drosophila using liposomes. Liposomes fluorescently-labelled with Nile Red or GFP were used for optimisation of the delivery system. These were fed to adult Drosophila and fluorescence used to trace liposome absorption from the intestinal lumen and distribution throughout the fly. Two compounds were then encapsulated in liposomes and fed to adult Drosophila, the geroprotector trametinib and the unpalatable compound paraquat. Both treatments displayed physiological and molecular responses in flies equivalent to conventional oral administration, with paraquat encapsulated in liposomes masking its taste. This liposome mediated drug delivery system has great potential as a drug screening system with further development needed for upscaling to longevity experiments.