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.

Date of Award	2021
Original language	English
Supervisor	Cathy Slack (Supervisor) & David Poyner (Supervisor)