A Role for Metabotropic Glutamate Receptors in Healthy Ageing

Abstract

The proportion of older individuals globally is increasing. This results in an increase in socioeconomic costs as more people are living long enough to suffer from the detrimental effects of ageing such as chronic age-related diseases. Thus, there is an urgent need to understand the mechanisms that drive ageing and promote healthy ageing. Ageing research using simple model organisms has shown that ageing can be modulated by genetic and environmental factors and these interventions extend lifespan and improve health in evolutionarily distant organisms. In this thesis, the fruit fly, Drosophila melanogaster was used to study the role of metabotropic glutamate receptors (mGluR) in biological ageing. mGluRs are highly conserved G-protein coupled receptors activated by the amino acid, L-glutamate to modulate intracellular signal transduction cascades, including the PI3K and MAP/ERK signalling pathways which play evolutionary conserved roles in animal ageing. By utilising a null mutation of the gene encoding the single fly mGluR we have found that loss of mGluR activity in flies causes sex-specific differences on longevity. This sex-specific effect was found to be strain-specific and may be partly attributed to differences in DmGluRA mRNA levels. This study also aimed to elucidate the mechanism(s) by which loss of mGluR extends lifespan. Phenotyping studies revealed that the long-lived mutants were associated with several phenotypes including increased resistance to stress, body weight and differences in triglyceride usage under starvation conditions. The studies also appear to rule out some possible mechanisms for the lifespan extension associated with loss of mGluR in Drosophila such as dietary restriction and improvements in gut physiology. RNA-Seq analysis also identified several genes which change in expression as a response to loss of mGluR signalling, many of which may explain the phenotypes observed and so are potential mechanisms of longevity. Further studies are required to fully understand the mechanisms of lifespan extension but taken together, the results form a case for mGluR as a novel ageing regulator.