Cytokine signalling, nutrition, longevity, and muscle health

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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.