How food speaks to you: A new brain-gut axis for lifelong health.

我们吃的东西对我们的终身健康有重大影响。超重会导致多种疾病，其严重程度会随着年龄的增长而加剧。这使得了解饮食如何影响衰老过程，并找到控制它的方法，成为研究和公共卫生政策的一个重要优先事项。营养是众所周知的长寿调节剂。通过调节食物摄入可以延长寿命并改善与年龄相关的健康状况。饮食限制或间歇性禁食，甚至仅仅是通过闻到营养水平的变化。该项目研究了大脑对营养的感知与肠道等其他代谢组织（今后称为脑肠轴）变化之间的联系，并将其与饮食行为、代谢健康和衰老联系起来。确定与营养-脑-肠反应有关的新分子靶点，为治疗与年龄相关的疾病和改善健康提供了切实可行的方法。最近，Taylor和Tullet实验室独立发现并发表了两个令人信服的候选途径，将营养感知与年龄相关的健康联系起来。这些是NF-E2相关转录因子（Nrf）和内质网（ER）的未折叠蛋白反应（UPR）。这项合作资助汇集了我们过去的工作和新的初步数据，以完成这项工作。我们假设Nrf在神经元中传递有关饮食的信息并调节肠道中UPR的激活。然后，这一系列事件将控制营养调节的喂养行为、新陈代谢和与年龄相关的健康。这里提出的工作将使用线虫秀丽隐杆线虫来研究这两种途径之间的脑肠关系。蠕虫是完美的，因为它有一个现成的遗传工具包，包括：突变体，使我们能够研究特定基因/分子的功能；荧光报告器让我们看到分子在何时何地被打开或关闭；以及一个完整的神经系统，这样我们就能准确地知道哪些神经元会相互传递信号。这种有用且经济的模型将使我们能够建立从食物感知到神经元Nrf信号传导到UPR激活的事件的分子序列。此外，这些小动物是饮食行为、与年龄相关的健康和寿命的极好模型，使我们能够探索分子变化对这些过程的影响。确定将营养信息与对代谢健康和衰老的影响联系起来的分子机制，将有助于开发利用这些机制或针对其特定分子功能的疗法，以便从治疗上操纵衰老和健康，为延缓和治疗饮食引起的疾病和其他与年龄有关的非传染性疾病提供途径。

What we eat has a major impact on our lifelong health. Being overweight causes multiple diseases, the severity of which is exacerbated by age. This makes understanding how diet impacts the ageing process, and finding ways to manipulate it, an important priority for research and public health policy. Nutrition is a known modulator of longevity. It is possible to increase lifespan and improve age-related health by modulating food intake eg. dietary restriction or intermittent fasting, or even by simply smelling changes in nutrient levels. This project investigates what connects the sensing of nutrition by the brain with changes to other metabolic tissues like the gut (henceforth referred to as the brain-gut axis), and links this to eating behaviours, metabolic health, and ageing. Identifying new molecular targets implicated in the nutrition-brain-gut response provides tangible methods to treat age-associated pathologies and improve health. Recently the Taylor and Tullet labs independently identified and published two compelling candidate pathways that connect nutrient perception to age-related health. These are the NF-E2 related transcription factor (Nrf) and the Unfolded Protein Response (UPR) of the endoplasmic reticulum (ER). This collaborative grant brings together our past work and new preliminary data to complete the picture. We hypothesise that Nrf acts in neurons to communicate information about diet and regulate UPR activation in the gut. This sequence of events will then control nutrient regulated feeding behaviours, metabolism and age-related health.The work proposed here will use the nematode worm Caenorhabditis elegans to investigate the brain-gut relationship between these two pathways. The worm is perfect for this as it comes with a ready-made genetic toolkit, including: mutants that allow us to study the function of specific genes/molecules; fluorescent reporters allowing us to see where and when molecules are switched on or off; and a fully mapped nervous system so that we know exactly which neurons signal to each other. This useful and cost-effective model will allow us to establish the molecular sequence of events from the sensing of food, to neuronal Nrf signalling, to UPR activation. In addition, these tiny animals are excellent models for eating behaviour, age-related health, and lifespan, allowing us to probe the impact of molecular change on these processes. Identifying the molecular mechanisms that connect nutrient information with effects on metabolic health and ageing would enable the development of therapies that harness these mechanisms or target their specific molecular functions in order to therapeutically manipulate ageing and health, providing avenues to delay and treat both diet-induced and other non-communicable diseases associated with age.