# Genetic and Pharmacological Inhibition of Metabotropic Glutamate Receptor Signalling Extends Lifespan in Drosophila

## TL;DR

Blocking a specific brain receptor in fruit flies extends their lifespan and improves health, suggesting a new target for anti-aging treatments.

## Contribution

The study shows that inhibiting metabotropic glutamate receptors in fruit flies extends lifespan and identifies a key protein involved in this process.

## Key findings

- Genetic or drug inhibition of DmGluRA increases lifespan in female fruit flies.
- Reduced ribosome biogenesis and improved stress tolerance are linked to this longevity.
- The effect depends on the Fragile X Mental Retardation Protein (FMRP).

## Abstract

Invertebrate models have been instrumental in advancing our understanding of the molecular mechanisms of ageing. The isolation of single gene mutations that both extend lifespan and improve age‐related health have identified potential targets for therapeutic intervention to alleviate age‐related morbidity. Here, we find that genetic loss of function of the G protein‐coupled metabotropic glutamate receptor (DmGluRA) in Drosophila extends the lifespan of female flies. This longevity phenotype was accompanied by lower basal levels of oxidative stress and improved stress tolerance, and differences in early‐life behavioural markers. Gene expression changes in DmGluRA mutants identified reduced ribosome biogenesis, a hallmark of longevity, as a key process altered in these animals. We further show that the pro‐longevity effects of reduced DmGluRA signalling are dependent on the fly homologue of Fragile X Mental Retardation Protein (FMRP), an important regulator of ribosomal protein translation. Importantly, we can recapitulate lifespan extension using a specific pharmacological inhibitor of mGluR activity. Hence, our study identifies metabotropic glutamate receptors as potential targets for age‐related therapeutics.

We show that genetic and pharmacological inhibition of the metabotropic glutamate receptor, DmGluRA extends Drosophila lifespan, improves stress tolerance and alters early‐life locomotion. Several markers indicative of reduced ribosomal biogenesis, a hallmark of longevity, were also detected in these flies. DmGluRA post‐transcriptionally modulates the expression of the Fragile X Mental Retardation Protein (FMRP), a regulator of ribosomal protein translation, with FMRP identified as key for DmGluRA‐dependent longevity. Our study therefore highlights metabotropic glutamate receptors as potential targets for age‐related therapeutics.