Elucidating the role of Insulin/IGF-like signalling in the response of lifespan to dietary restriction in Drosophila melanogaster

Griffiths, Tia and Broughton, Susan (2023) Elucidating the role of Insulin/IGF-like signalling in the response of lifespan to dietary restriction in Drosophila melanogaster. Masters thesis, Lancaster University.

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Abstract

MutaDons within the insulin/IGF-like signalling (IIS) pathway have been shown to influence lifespan in model organisms such as Caenorhabdi;s elegans, Drosophila melanogaster, and Mus musculus. Specifically, reducDons in IIS, both systemic and Dssue-specific, have been associated with increased lifespan, however some modulaDons have negaDvely impacted healthspan, including reproducDve and behavioural health. In parDcular, the pan-neural reducDon of IIS negaDvely affects the senescence of exploratory walking and negaDve geotaxis in Drosophila despite extending lifespan. The pan-neural effects of IIS reducDon were hypothesised to be the sum of the posiDve, negaDve, and neutral effects of reduced IIS within individual neuronal subtypes and recent research supports this hypothesis. One recent study found that reducing IIS in specific neuronal subtypes in Drosophila resulted in varying effects on lifespan and locomotor senescence. Reducing IIS in serotonergic neurons was the only modulaDon invesDgated capable of extending lifespan, and it did so without negaDvely impacDng locomotor senescence. This project addresses two hypotheses: 1) the response to dietary restricDon involves insulin/IGF-like signalling in serotonergic neurons and therefore the response of flies with reduced IIS in serotonergic neurons will be reduced; and 2) reducing IIS in serotonergic neurons will alter serotonergic signalling to the IPCs resulDng in altered DILP expression and/or secreDon. To address these hypotheses, we used survival assays with standard, dietary restricDon, fully fed, and low nutrient (0.1 x yeast) food condiDons, immunohistochemical analysis of proteins in fly brains, and qPCR of fly heads. We also invesDgated other behaviours and phenotypes which could have been influenced by reduced serotonergic IIS including oxidaDve stress resistance, starvaDon resistance, negaDve geotaxis, feeding behaviour, and fecundity. The results showed that reduced serotonergic IIS increased lifespan in females on DR and SY diets and increased the lifespan of males on 0.1% yeast starvaDon and FF diets. No negaDve effects of reduced serotonergic IIS on stress resistance, negaDve geotaxis, or female fecundity were observed. AddiDonally, DILP2 and DILP5 expression was not altered in females with reduced serotonergic IIS, however, serotonin was. Together, the data suggest that the lifespan extension observed in females is likely not due to a modulaDon of the insulin producing cells (IPCs) and could be the result of altered serotonin signalling, however, further research is needed to determine the exact mechanism.