Identification of novel anti-ageing genes as drug targets using Drosophila melanogaster as a model

Murali, Poorna and Clancy, David (2025) Identification of novel anti-ageing genes as drug targets using Drosophila melanogaster as a model. PhD thesis, Biomedical and Life Sciences.

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Abstract

Ageing is a complex process shaped by genetic, environmental, and stochastic factors. It is one of the major causes of cancer, cardiovascular, and neurodegenerative diseases. Identifying the underlying mechanisms and the genes that contribute to longevity would alleviate the socio-economic burden of age-related diseases. This study focused on identifying novel anti-ageing genes and understanding their roles in lifespan and neuromuscular function using Drosophila melanogaster to use as potential drug targets. A previous study in our lab generated long-lived strains (S1, S2) through artificial selection, achieving a 15% increase in lifespan compared to controls (C1, C2). RNASeq analysis of differentially expressed genes (DEGs) identified candidate anti-ageing genes requiring phenotypic testing and validation. Using the GeneSwitch expression system, RNAi knockdown and overexpression of nine candidate genes were tested for effects on lifespan and negative geotaxis, a measure of neuromuscular function. However, no significant changes were observed, suggesting that the role of these genes in lifespan extension is not significant under the tested conditions. Challenges included validating gene expression, fungal infections, and technical issues with the GeneSwitch system, such as leaky drivers and mosaic expression. The results emphasise the complexity of ageing and the interplay between genetic and environmental factors. Future studies should focus on tissue-specific RNASeq and gene expression, expanded sample sizes, and multi-gene manipulations to explore synergistic effects. Combining transcriptomic, proteomic, and metabolomic analyses could provide deeper insights into ageing mechanisms. This study lays the groundwork for further exploration of genetic determinants of ageing and potential therapeutic strategies.