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

Dravecz, Nikolett and Broughton, Susan and Shirras, Alan (2020) Insulin/IGF-like signalling and brain ageing in Drosophila melanogaster. PhD thesis, Lancaster University.

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Abstract

Human life expectancy has been steadily increasing since the mid-nineteenth century in developed countries, mainly due to improved public health and lifestyle changes, which has led to the increasing prevalence of age-related diseases. Understanding the biological mechanisms of ageing is essential to improve human health at older ages and extend health-span. Reduced Insulin/IGF-like signalling (IIS) improves longevity and some measures of health-span in model organisms, such as C. elegans, Drosophila melanogaster and Mus musculus, suggesting an evolutionarily conserved role. Recent studies, however, have found a disconnection between lifespan extension and behavioural health-span. It was recently shown that selective reduction of IIS in Drosophila neurons extended female lifespan but did not improve negative geotaxis senescence and had a detrimental effect on exploratory walking senescence in both sexes. This project addresses the following two hypotheses: (1) the negative effects of reduced IIS on behavioural senescence may be due to detrimental effects on neuronal function at older ages that outweigh any positive effects of reduced IIS on neuronal ageing; and/or (2) individual neuronal subtypes respond differently to IIS changes, thus the behavioural outcomes of pan-neuronal IIS reduction are the sum of a mixture of positive, negative and neutral functional effects. We found that adult-specific pan-neural IIS reduction is sufficient to extend female lifespan and result in detrimental but reversible effects on behavioural senescence. The data suggest that the detrimental behavioural effects of reduced pan-neuronal IIS are likely due to a reduction in neuronal function and are not due to accelerated neuronal ageing. Altered Drosophia Insulin-like preptide (dilp) expression observed in response to adult pan-neuronal IIS reduction in females may suggest an endocrine mechanism of lifespan extension involving modulation of dilps from the brain insulin producing cells and fat body. IIS reduction in specific neuronal subtypes either does not affect or has detrimental effects on lifespan and health-span suggesting that individual neuronal subtypes do respond differently to IIS changes. We did not find evidence that the ageing of neurons is altered by reduced IIS and further work is needed to elucidate the molecular mechanisms involved in lifespan extension and reduced neuronal function due to reduced pan-neuronal IIS.