Cytokine signalling, nutrition, longevity, and muscle health

在人类和其他动物中，营养对生物学有着强大而复杂的影响。即使在没有肥胖或明显营养不良的情况下，含有不同数量的糖、脂肪或蛋白质的饮食也会对生理产生重要影响；例如，去年有报道称，饮食中富含蛋白质的人往往比其他人死得早。在许多情况下，饮食对生理的影响机制尚不清楚。我们已经开始在果蝇身上分析这个问题；在果蝇身上做这项工作的好处是，我们可以非常快速地测试营养的许多方面的影响，而且相对便宜。许多生理调节机制在果蝇和人类之间是保守的。在我们的初步数据中，我们表明在果蝇中，巨噬细胞-免疫系统的细胞-是营养感知系统的关键部分。巨噬细胞似乎检测到饮食中的蛋白质，并产生一种信号，被肌肉接收；这个信号导致肌肉对胰岛素的反应减弱。巨噬细胞传递给肌肉的信号对于果蝇维持正常寿命和低糖饮食至关重要。我们在这里提出的实验有两个部分。在第一部分中，我们测试了巨噬细胞中已知对膳食蛋白质有反应的途径的生物学作用。在第二部分中，我们使用多种方法来探索巨噬细胞对饮食的感知与肌肉生理学之间的信号通路。我们的初步结果，结合拟议的实验，代表着我们对身体如何感知和反应饮食成分的认识迈出了戏剧性的一步。这是巨噬细胞在正常生理中的全新作用，揭示了膳食蛋白质影响寿命和肌肉生理的全新途径。我们的工作将对年龄相关疾病、炎症性疾病和营养生理学具有重要意义。

In humans and other animals, nutrition has strong and complex effects on biology. Diets with different amounts of sugar, fat or protein can have important effects on physiology, even in the absence of obesity or obvious malnutrition; for example, it was reported last year that people who eat diets high in protein tend to die younger than others. In many cases, the effects of diet on physiology work by mechanisms that are not clear. We have begun to analyse this problem in fruit-flies; the advantage of doing this work in flies is that we can test the effects of many aspects of nutrition very quickly and relatively inexpensively. Many of the mechanisms of physiological regulation are conserved between flies and people.In our preliminary data, we show that in fruit-flies, macrophages - cells of the immune system - are a critical part of the nutrient sensing system. Macrophages appear to detect dietary protein and produce a signal that is received by muscles; this signal causes muscles to become less responsive to insulin. The signal from macrophages to muscles is critically important in allowing flies to live a normal lifespan and to be able to survive on diets that are low in sugar.The experiments we propose here have two parts. In the first part, we test the biological role in the macrophage of a pathway known to be responsive to dietary protein. In the second part, we use a variety of approaches to explore the signalling circuitry that connects macrophage sensing of diets with muscle physiology.Our preliminary results, combined with the proposed experiments, represent a dramatic step in our knowledge of how the body senses and responds to dietary components. This is a fundamentally new role for macrophages in normal physiology and reveals an entirely new way that dietary protein can affect lifespan and muscle physiology. Our work will have significant implications regarding age-related disease, inflammatory disease, and nutritional physiology.