Can we extend lifespan in Drosophila by changing gene expression or by drug treatments?

Islam, Mahjabeen and Clancy, David (2026) Can we extend lifespan in Drosophila by changing gene expression or by drug treatments? Masters thesis, Lancaster University.

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Abstract

Aging is a complex process involving physiological and functional changes in cellular activities, genetic pathways, and overall organismal integrity. The increasing global population and longer life expectancy have indeed created a growing urgency to find ways to extend health span. Considering health span not solely, life span is crucial to reduce the social and economic burden of aging populations. Number of years a person lives in good health free from any chronic disease and disability is more important that the total number of years he lived. A longer life accompanied by more years of chronic illness, frailty, and dependency leads to escalating medical expenses, long-term care needs, and increased public spending. This means not just adding years to life but adding healthy years is important. Studying gene expression is a powerful tool to understand aging. Ideally, aim of this study was to overexpress a specific gene at defined times within an organism. The GAL4 GeneSwitch system, a modified version of the UAS/GAL4 system, allows for such control over gene expression. It uses the drug RU486 to activate a modified GAL4 protein, enabling both spatial (tissue-specific) and temporal (time-controlled) gene regulation. This system can be used to manipulate genes potentially relevant to aging. In this study, GeneSwitch system was employed to investigate the effects of gene manipulation on lifespan and climbing speed in male fruit flies (Drosophila melanogaster). Glyceraldehyde-3-phosphate dehydrogenase (gapdh 1) is known for its role in glycolysis and is called moonlight protein because of its multifunctional activities as it acts as a transcription factor and influences cell survival and proliferation. It was used in this research because its expression decreases with age quite a lot, both sexes, and it’s expressed ubiquitously and fairly high levels (Flybase). In the first experiment, the Glyceraldehyde-3-phosphate dehydrogenase (gapdh) gene was overexpressed under the control of tissue-ubiquitously expressing promoters (Actin and daughterless). Although gapdh was not overexpressed significantly in the experiment. So, overall lifespan was not significantly extended, flies carrying only the UAS- gapdh transgene (without the GeneSwitch driver) did show a longer lifespan. Interestingly, flies with the GeneSwitch driver alone (ActinGS-255B) displayed increased activity compared to another fly strain (daughterless). The results showed no increase in lifespan of flies. These results highlighted the importance of further research into the gapdh gene and further explanation of its role in ageing. Anti-aging drug therapy is considered one of the most promising strategies to tackle the effects of ageing. Combination of different drugs can extend healthy life span when they target age-related mechanisms. In the second project, four different drugs (alagebrium, baicalein, lithium, bathophenanthroline disulfonic acid), individually and in combination were used to investigate their effect on the lifespan of two wildtype fly strains (Lancaster and Dahomey). 1) Alagebrium is known as cross link breaker formed by advanced glycation end products (AGEs) which are linked to aging. 2) Baicalein is a flavonoid with antioxidant, antibiotic, and free radical scavenging properties. 3) One of the most significant roles of lithium is inhibition of glycogen synthase kinase-3 (GSK-3) which is a tau protein kinase-1 which regulate tau phosphorylation in Alzheimer disease and reported to extend lifespan of Drosophila by inhibiting glycogen synthase kinase-3 (GSK-3) via activation of transcription factor nuclear factor erythroid 2 related factor (NRF-2). 4) Bathophenanthroline disulfonic acid (BPS) is an iron chelator that reduces lipid peroxidation, a damaging process in cells. The results showed no significant impact on lifespan for most drug combinations. However, a combination of three drugs (alagebrium, lithium, and baicalein) did lead to a slight increase (3%) the median lifespan of flies from the Dahomey strain (p=0.05). In wDah flies, lithium itself significantly increased the median life span of wDah flies by 3% and significantly extended the median lifespan of Lancaster flies by 6% to 67 days (P<0.05). The results suggest that these drugs and their combinations did not increase lifespan drastically and they are not worth pursuing, and that the papers using lithium overestimated its effects. As well as it will likely a step towards using novel drugs to extend healthy life span in future.