Investigating the metabolic effects of RAS/MAPK pathway inhibition during ageing

Abstract

Ageing associated pathophysiology as obesity is on the rise in the last 100 years, coupled with increased lifespan, at the detriment of healthspan, led to economic and social burdens on a population scale. Therefore, improving the study of obesity and associated symptoms is essential to healthy ageing. RAS/MAPK pathway is a nutrient sensing pathway involved in cell survival and differentiation in Drosophila. Previous work focused on RAS/MAPK pathway involvement in cancer. Recently, studies have highlighted the importance of RAS/MAPK pathway, specifically genetic inhibition, in the process of ageing and lipid metabolism. However, little is known regarding the pharmacological effects of RAS/MAPK pathway inhibition and its effects on obesity. The aim of this thesis was to utilize Drosophila as a model organism to gain knowledge of pharmacological inhibition of RAS/MAPK pathway in response to obesity. In this thesis, unpublished data showed a lifespan extending and glyceride lowering effect of RAS/MAPK pathway using a MEK specific inhibitor, trametinib, through an unknown mechanism of action. Phenotypic analysis of trametinib treated flies in response to diet intervention showed glyceride reducing effect of trametinib through a lipid metabolism independent mechanism, additionally uric acid and Malpighian tubule deposits were reduced. Subsequent RNA-sequencing analysis identified subsets of genes that show interaction as potential mechanisms through which trametinib elicits its effects. Analysis of publicly available RNA-sequencing dataset found significant overlap of sugar-responsive genes, a subset of which were also altered by trametinib. Lipidomics analysis revealed changes in glyceride and phospholipid lipid profile of trametinib treated flies. Summarily, novel molecular mechanisms of action were discovered of the beneficial phenotypic effects of trametinib in response to diet- and age-dependent obesity. Ultimately, a more in-depth ‘multi’-omics approach of effects of trametinib will allow for identification of potential pharmaceutical targets to treat diet- and age-dependent obesity.