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

五环三萜熊果酸是一种生物活性分子，已从许多食用植物中分离出来。在我们的初步工作中，我们长期给予模式生物果蝇补充熊果酸的饮食，并发现，据我们所知，第一次，熊果酸促进寿命和改善与年龄相关的果蝇运动活性下降。通过使用功能强大的果蝇模型，当前项目提案的目的是阐明潜在的分子机制。我们假设熊果酸作为一种饮食/能量限制模拟物，因为它已知的降血糖和降血脂作用，从哺乳动物系统的报告。为此，我们将采取三种做法。首先，我们将揭示熊果酸是否会影响衰老果蝇的身体组成、能量消耗和/或能量代谢。将确定碳水化合物和脂质代谢的关键因子和选定效应分子以及相关营养物传感途径的表达/活性。其次，我们将研究熊果酸是否在不同的饮食方案（高脂肪饮食，高糖饮食，热量限制和不同的碳水化合物来源）下促进长寿和健康衰老。第三，熊果酸将在D.研究具有不同寿命决定遗传背景的黑腹果蝇突变体对生存和健康寿命的影响，将揭示其与purons相互作用的途径。此外，通过功能衰老分析，我们将检查补充熊果酸是否能够改善D的其他参数。黑腹动物的一些特征是经历逐渐的年龄依赖性衰退，如学习和记忆、免疫状态、肠道完整性、线粒体功能和应激抵抗力。因此，我们的研究将有助于更好地了解衰老过程和熊果酸的生理特性，并有助于评估植物化学物质在营养和衰老研究中的潜力。

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.