The Effects of Reduced Insulin/IGF-like Signalling in the CNS on Lifespan, Brain Ageing and Stress Resistance in Drosophila melanogaster

Shaw, Tommy and Broughton, Susan (2021) The Effects of Reduced Insulin/IGF-like Signalling in the CNS on Lifespan, Brain Ageing and Stress Resistance in Drosophila melanogaster. Masters thesis, Lancaster University.

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Abstract

Single gene mutations have been discovered with the capability to improve lifespan in organisms such as Drosophila melanogaster, Caenorhabditis elegans, and Mus musculis. The first of these mutations was reduction of the Insulin/Insulin-like growth factor-1 (IGF-1) signalling (IIS) pathway. Tissue specific IIS reduction is sufficient to extend lifespan, in Drosophila pan-neural IIS reduction improves lifespan but negatively effects locomotor behavioural senescence. Further study has shown disconnection between the effects on lifespan and healthspan. It has been hypothesised that due to the differential IIS sensitivities of individual neuronal subtypes, the overall effects of pan-neural IIS reduction on lifespan and healthspan are the summation of positive, negative, and neutral effects on each subtype. To further investigate this hypothesis, previous work has been completed which studied the lifespan and behavioural effects of IIS reduction in specific neuronal subtypes. The four subtypes tested so far are Dopaminergic, Glutamatergic, Cholinergic, GABAergic, none of which have been found to positively affect longevity or behavioural senescence. The aim of this project is to investigate the lifespan and behavioural effects of IIS reduction specifically in serotonergic neurons in D. melanogaster and to further understand effects of pan-neural IIS reduction on stress resistance. We found that IIS reduction in serotonergic neurons is sufficient to extend lifespan in female flies but has no effect on male lifespan, similarly to the effects of pan-neural IIS reduction. Unlike pan-neural IIS reduction, serotonergic IIS knockdown is not detrimental to exploratory walking senescence, suggesting that this method is not damaging to the neural circuitry underlying those behaviours. The results of this study also show that pan-neural IIS reduction does not affect oxidative stress resistance, constitutive IIS reduction in neurons increases starvation resistance in females, but adult-specific pan- neural IIS reduction does not affect starvation resistance.