Insulin/IGF-like signalling and brain ageing in Drosophila melanogaster

With the steady increase of human lifespan in many countries, understanding the underlying mechanisms of aging has become a crucial research interest in order to promote human health and longevity and prevent age-associated diseases. Over the last few decades, many studies have shown that ageing is modulated by the evolutionarily conserved nutrient-sensing Insulin/IGF-like signalling (IIS) pathway. IIS interacts with multiple cellular processes, including cell growth, development, metabolic homeostasis, fecundity and stress resistance. Evidence has revealed a strong connection between systemically reduced IIS and extension of lifespan, ranging from invertebrate model organisms, Drosophila melanogaster, and Caenorhabditis elegans, to mammalians, mice and even humans. Systemic mediation of components in the IIS pathway has resulted in reduced fecundity, increased lifespan and accumulation of carbohydrates and lipids. However, there is still much to be discovered regarding the regulation of different IIS components in specific tissues or organs and their roles in ageing and longevity. Overexpression of dPTEN or dFOXO (the antagonistic regulators of the IIS pathway), systemically or tissue-specifically, is reported to extend lifespan or delay specific tissue or organ ageing such as muscle and cardiac ageing. However, little is known about the role of IIS in neuronal ageing. The effects of altered IIS on all neurons in Drosophila was recently tested using the insulin receptor dominant-negative model (elavGAL4/UAS-InRDN). This project aims to continue investigating the role of reduced IIS in neurons on brain functions, ageing, and longevity using inducible overexpression of PTEN to reduce IIS in the D. melanogaster model and to determine the role of reduced IIS during development and adulthood. The effects are tested through lifespan, behavioural senescence(definition) (negative geotaxis, exploratory walking, and sleeping behaviours), biochemistry and cellular experiments including stress resistance, glycogen, and lipid content assays, and apoptosis assay. Our results confirm that IIS modulated lifespan and healthspan(definition) independently and reducing IIS in neurons caused detrimental functional effects in flies.