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，已从多种食用植物中分离得到。在我们的前期工作中，我们对模式生物果蝇黑腹果蝇进行了长期补充熊果酸的饮食，并首次发现，据我们所知，熊果酸延长了果蝇的寿命，改善了与年龄相关的果蝇运动活动的下降。通过使用强大的果蝇模型，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饮食/能量限制的模拟物，是因为哺乳动物系统中已知的其降血糖和降血脂作用。为此，我们将遵循三个途径。首先，我们将揭示熊果酸是否会影响衰老果蝇的身体成分、能量消耗和/或能量代谢。将确定碳水化合物和脂肪代谢的关键因素和选定的效应分子以及相关营养感知途径的表达/活性。其次，我们将研究熊果酸在不同饮食方案(高脂肪饮食、高糖饮食、限制卡路里和不同碳水化合物来源)下是否促进长寿和健康衰老。第三，熊果酸将在具有不同寿命的黑腹果蝇突变体中进行测试-确定其对生存和健康寿命的影响的遗传背景，这将揭示推测的相互作用的途径。此外，通过使用功能衰老分析，我们将检查补充熊果酸是否能够改善经历年龄相关性逐渐下降的其他参数，如学习和记忆、免疫状态、肠道完整性、线粒体功能和应激抗性。因此，我们的研究将有助于更好地了解熊果酸的老化过程和生理特性，并将有助于评估这种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.