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

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Diet and nutrition are known modulators of age-related health, and many diseases of ageing are exacerbated by poor diet and obesity. Identifying new molecular targets implicated in nutritional responses can therefore provide new routes to treat age-associated pathology. Two compelling candidates for connecting nutrient perception to age-related health are the NF-E2 related transcription factor (Nrf) and the Unfolded Protein Response (UPR). Both pathways influence metabolism and ageing in response to diet, have key roles in the nervous system, and regulate organism-wide responses. Based on published and preliminary data from our labs, we hypothesise that Nrf acts in neurons to communicate information about nutrition and regulate UPR activation in distal tissues. These events would connect the nutritional environment to metabolic tissues via a novel brain-gut axis. In turn this will control eating behaviour, metabolism and age-related health.

The proposed work will establish the relationship between these pathways and determine how they allow neurons to communicate nutrient status to peripheral tissues. This will be achieved using the nematode C. elegans, a tractable model system with established toolkits. We will use classical genetics, transgenic reporters, RNAseq, RNAi/CRISPR screening, and behavioural, metabolic and longevity assays to address 3 objectives: 1) Define the role of neuronal Nrf in nutrient regulated UPR activation; 2) Identify the neuronal circuit underlying the Nrf-UPR interaction; and 3) Determine the role that Nrf-UPR signalling plays in determining feeding behaviour, metabolic state and lifespan. This will identify new, fundamental mechanisms by which nutrient perception is connected to organism-wide effects, and relate this to diet-induced disease as well as age-related health. Evolutionary conservation of these pathways means that this will ultimately provide significant, translatable potential for the development of novel therapeutics.