Programming of lifespan by insulin/IGF-like signalling in Drosophila.

在我们的社会中，老年人的比例正在稳步上升。由于年龄是许多衰弱的慢性疾病的主要风险因素，这种人口结构的变化正在导致不断增加的人类和社会经济成本。了解衰老的生物学是一个关键的研究重点，因为它有可能为我们提供到老年时保持健康的手段。早期营养可能会影响老年人随后的健康。虽然这一现象的存在得到了大量流行病学证据的支持，并得到了哺乳动物直接实验的证实，但早期营养环境和年龄相关表型之间的机制联系仍然不清楚。我们最近使用果蝇黑腹果蝇来阐明年轻人饮食影响他们随后衰老的机制。我们发现，相对较短的时间暴露在富含糖的饮食中会激活胰岛素/IGF样信号(IIS)，抑制转录因子dFOXO来规划成年人的寿命，尽管饮食有所改善，但仍会缩短后续的生存时间。IIS途径在所有动物中都存在。它向动物发出营养状况的信号，以微调其生理。IIS途径的重要性明显体现在它在衰老中所起的作用：抑制IIS活性可以延长所有受试动物的寿命。同时，该途径也是人类代谢健康的重要决定因素。我们的初步数据表明，在果蝇的成年期早期，不依赖饮食干预，直接调节这一途径足以规划随后的寿命。动物对营养的反应是复杂的，由几个信号通路同时调节对多种饲料成分的相对和绝对量的反应。为了开始处理这种复杂性，我们建议直接检查分子机制，通过这些机制，IIS在成年早期的调节可以塑造果蝇随后的寿命。这将为我们提供一个更简单、更容易处理的实验系统，专注于单一的、相关的营养信号传递途径。反过来，这些发现将开始构建一幅连贯而全面的图景，说明早期营养如何影响衰老。我们最近的发现表明，仅在苍蝇的脂肪体(相当于哺乳动物的脂肪和肝脏)中短期调节IIS活性就足以改变动物随后的寿命。我们将确定是否有其他器官可以引起对衰老的长期影响。我们还将确定该途径的哪些效应器起作用。我们和其他人的工作揭示了IIS调制对动物生理产生长期影响的最有可能的机制：IIS的活动似乎能够改变染色质，染色质是动物遗传物质的包装，从而对基因表达产生长期影响。我们将确定IIS调节对相关成人组织中染色质结构和长期基因表达的影响。我们和其他团队已经确定，几种能够修改或重新组织染色质的酶参与了IIS途径。我们将研究这些基因中是否有任何基因调节IIS活性的长期影响。总之，该项目将阐明IIS水平的相对短期变化如何在成年动物体内引起长期影响。这将帮助我们理解早期营养如何对人类衰老产生影响。从长远来看，这些知识有可能为我们提供手段，确保人类在整个生命过程中的健康和福祉。

The proportion of older individuals is steadily increasing in our societies. Since age is the main risk factor for a number of debilitating, chronic diseases, this demographic change is resulting in ever-increasing human and socioeconomic costs. Understanding the biology of ageing is a key research priority because it has the potential to provide us with means to maintain health into old age. Early-life nutrition can impact subsequent health in older humans. While the existence of this phenomenon is supported by a wealth of epidemiological evidence and corroborated by direct experimentation in mammals, the mechanistic links between early nutritional environment and age-related phenotypes remain unclear. We have recently used the fruit fly Drosophila melanogaster to elucidate the mechanisms whereby the diet consumed by young adults influences their subsequent ageing. We found that a relatively short exposure to a diet rich in sugar activates insulin/IGF-like signalling (IIS) inhibiting the transcription factor dFOXO to programme adult lifespan, curtailing subsequent survival despite a dietary improvement. IIS pathway is present in all animals. It signals the animal's nutritional status to fine-tune its physiology. The importance of the IIS pathway is manifest in the role it plays in ageing: inhibition of IIS activity promotes longevity in all animals tested. At the same time, the pathway is a important determinant of human metabolic health. Our preliminary data show that modulating this pathway directly, independently of a dietary intervention, in early adulthood in Drosophila is sufficient to programme subsequent lifespan. Animal responses to nutrition are complex, simultaneously mediated by several signalling pathways in response to relative and absolute amounts of multiple dietary components. To start tackling this complexity, we propose to examine directly the molecular mechanisms whereby modulation of IIS in early adult life can shape subsequent longevity in Drosophila. This will provide us with a simpler, more tractable experimental system, focused on a single, relevant, nutrient-signalling pathway. In turn, the findings will start building a coherent and comprehensive picture of how early-life nutrition affects ageing. Our recent findings show that short-term modulation of IIS activity in just the fat body of the fly (equivalent to mammalian adipose and liver) is sufficient to change the animal's subsequent longevity. We will determine if there are other organs from which the long-term effects on ageing can be elicited. We will also determine which effectors of the pathway play a role. Work by us and others has revealed the most-likely mechanism for the long-term effects of IIS modulation on animal physiology: IIS activity appears able to change chromatin, which is the packaging of the animal's genetic material, with long-term consequences for gene expression. We will determine the impact of IIS modulation on chromatin structure and long-term gene expression in the relevant adult tissues.We and other groups have established that several enzymes capable of modifying or re-organising chromatin are engaged by the IIS pathway. We will examine whether any of these genes are mediating the long-term effects of IIS activity.In summary, the project will elucidate how relatively short-term changes in the levels of IIS can cause long-term effects in an adult animal, in vivo. This will help us understand how early-life nutrition can have an impact on human ageing. This knowledge, in the long-term, has the potential to provide us with means to ensure human health and wellbeing throughout the life course.