Metabotropic glutamate receptor signalling: a new drug target for longevity.

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As we age, our susceptibility to multiple long-term diseases substantially increases. This has a significant impact on quality of life for older people as well as social and economic costs to our society, particularly given the current global rise in human life expectancy. Thus, new ways to reduce the burden of ill health in older people are urgently required.An important finding in the field is that health during ageing can be modulated by both genetic and environmental factors. Furthermore, similar biological processes regulate healthy ageing across evolutionarily diverse species. We can therefore use simple laboratory models such as the fruit-fly, Drosophila melanogaster, to effectively study the mechanisms that drive human ageing and age-related diseases. This innovative approach will identify new pharmacological targets that modulate the underlying cause of disease - ageing itself.We have recently discovered that we can improve healthy ageing in Drosophila if we inhibit the activity of a specific cell-surface receptor, the metabotropic glutamate receptor or mGluR. These receptors are present in all animals. They bind to the amino acid L-glutamate to activate a cascade of cell signalling events. The activity of these receptors has already been shown to have important implications for human health as highlighted by their involvement in several neurological disorders. However, we do not yet understand the mechanisms by which inhibition of mGluR activity improves healthy ageing. This information is essential to realise the full functional significance of this new ageing regulator.In this project, we will use Drosophila as a simple model to define how mGluR signalling impacts on age-related health. We will switch off mGluR expression in specific tissues and at certain time-points during the lifecourse of the animals to identify where and when mGluR activity influences health during ageing. We will disrupt receptor function in more precise ways by changing specific amino acids within the protein sequence. We will also alter the activity of various downstream signalling molecules to determine how disruption of mGluR function leads to longer lifespan. Our preliminary data shows that as well as longevity, inhibition of mGluR function also promotes resistance to various stresses. These effects are associated with changes in the expression of important stress responsive genes. We will expand these studies to analyse the global changes in gene expression upon mGluR inhibition using RNA-sequencing. This will allow us to identify the physiological processes that are responding to mGluR inhibition to promote longevity. Lastly, we will use well-characterised pharmacological inhibitors of mGluR activity that are already used in the clinic for other purposes and feed them to adult flies to determine their age-dependent effects on longevity, a critical step in the development of these inhibitors for future therapeutics for age-related disease. Together, this knowledge will enable us to fully characterise a new evolutionarily conserved longevity regulator. This is an essential stage for the identification of new drug targets that could be used to treat multiple age-related diseases by targeting their common underlying cause - the biological processes of ageing - to promote human health and well-being across the lifecourse.