The molecular mechanisms underlying the longevity and health promoting effects of the triterpenoid ursolic acid in Drosophila melanogaster

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The pentacyclic triterpenoid ursolic acid is a bioactive molecule that has been isolated from numerous food plants. In our preliminary work, we chronically administered an ursolic acid-supplemented diet to the model organism Drosophila melanogaster and found, to the best of our knowledge for the first time, that ursolic acid promotes longevity and ameliorates the age-related decline of locomotor activity in the fruit fly. By employing the powerful fruit fly model, the aim of the current project proposal is to elucidate the underlying molecular mechanisms. We hypothesize that ursolic acid acts as a dietary/energy restriction mimetic because of its known hypoglycemic and hypolipidemic action reported from mammalian systems. To this end, we will follow three approaches. First, we will unravel whether ursolic acid affects the body composition, energy expenditure and/or energy metabolism of ageing flies. The expression/activity of key factors and selected effector molecules of the carbohydrate and lipid metabolism as well as of the related nutrient-sensing pathways will be determined. Second, we will examine whether ursolic acid promotes longevity and healthy ageing under different dietary regimens (high fat diet, high sugar diet, caloric restriction and different carbohydrate sources). Third, ursolic acid will be tested in D. melanogaster mutants possessing different lifespan-determining genetic backgrounds for its effect on survival and health span, which will reveal putatively interacting pathways. Moreover, by using functional senescence analyses we will examine whether supplementation of ursolic acid is able to improve additional parameters of D. melanogaster that undergo a gradual age-dependent decline such as learning and memory, immune status, gut integrity, mitochondrial function and stress resistance. Thus, our studies will lead to a better understanding of the ageing process and the physiological properties of ursolic acid and will help to evaluate the potential of the phytochemical in nutritional and ageing research.