Monosodium glutamate (MSG, sodium glutamate) – a common condiment – evokes mixed feelings. On one hand, glutamate enhances food umami and stimulates appetite; on the other, its sodium content causes "water-sodium retention," leading to edema and increased metabolic pressure on the heart and kidneys, making it a controversial ingredient.
Surprisingly, this debated molecule has sparked new waves in the anti-aging field. A recent study published in Aging Cell by UK researchers shows that inhibiting or disrupting the only metabotropic glutamate receptor (mGluR) in fruit flies – DmGluRA – extends the lifespan of female fruit flies by approximately 11%[1]. And its core anti-aging mechanism seems to be linked to ribosomes?
Research Article (Open Access)
Aging Cell
Title: Genetic and Pharmacological Inhibition of Metabotropic Glutamate Receptor Signalling Extends Lifespan in Drosophila
Authors: Cui Guan, Abigail Otchere, Mihails Laskovs, Irene Papatheodorou, Cathy Slack
First Published: February 12, 2025
DOI: https://doi.org/10.1111/acel.14500
Title: Genetic and Pharmacological Inhibition of Metabotropic Glutamate Receptor Signalling Extends Lifespan in Drosophila
Authors: Cui Guan, Abigail Otchere, Mihails Laskovs, Irene Papatheodorou, Cathy Slack
First Published: February 12, 2025
DOI: https://doi.org/10.1111/acel.14500
Part 1: Can a Neurotransmitter Receptor Combat Aging?
Beyond being the main component of MSG, glutamate is a key natural amino acid in many proteins and the most important excitatory neurotransmitter in the human body (a chemical that transmits signals in the nervous system). It is widely distributed in the central and peripheral nervous systems and participates in various physiological processes, including learning, memory, synaptic plasticity, neurogenesis, and neuroprotection[2].
Signal transmission requires both "senders" and "receivers." If glutamate is the "package," then glutamate receptors are the "recipients" – glutamate binds to these receptors to transmit information to the host cell, triggering a series of neural responses.
Glutamate receptors are divided into two major categories based on their functions:
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Ionotropic glutamate receptors (iGluRs)[3]: Analagous to a "gate." When bound to glutamate, the "gate" opens, directly mediating the rapid flow of ions (e.g., Na⁺, K⁺, Ca²⁺) between the inside and outside of the cell, causing rapid changes in membrane potential and participating in nerve impulse transmission between neurons.
Figure Note: Three types of ionotropic glutamate receptors (NMDA, AMPA, Kainate) – with details on agonist/antagonist and ion permeability (e.g., Ca²⁺ permeability conferred by arginine residues). -
Metabotropic glutamate receptors (mGluRs)[4]: More like a "glove." After binding to glutamate (the "ball"), they activate intracellular G-proteins to regulate intracellular signal transmission. Though slower-acting, they play an indispensable role in neuronal development, differentiation, and synaptic plasticity.
Figure Note: Metabotropic glutamate receptors (Group I: mGluR 1/5) – with post-synaptic expression (periphery) and downstream effects like increased kinase activity via G-protein βγ subunits.
The new study focuses on this "glove-like" receptor. Scientists found that the expression of the metabotropic glutamate receptor gene DmGluRA varies significantly with age: as fruit flies age, their DmGluRA expression levels decrease, leading to various consequences.
Figure Note: DmGluRA expression in different body parts of fruit flies (head, thorax, abdomen) – red for females, black for males – at different ages (D10/D25/D50, representing days post-eclosion).
For example, compared with the control group, female fruit flies with DmGluRA mutations showed a significant 11% extension in lifespan.
Figure Note: Survival curves of female fruit flies (wDah vs. 112b mutant) – showing enhanced longevity in the mutant group.
Figure Note: Survival curves of female fruit flies (wDah vs. 112b mutant) – showing enhanced longevity in the mutant group.
Part 2: A New Gene with Multifaceted Functions?
Is DmGluRA a new "longevity gene" linked to aging? To explore this, scientists used gene-editing technology to knock out the DmGluRA gene in fruit flies and observed changes in various physiological traits:
1. Enhanced Survival Under Extreme Conditions
In addition to the 11% lifespan extension, mutant fruit flies showed improved survival under "extreme" conditions (simulated starvation and oxidative stress):
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Starvation simulation: Mutant female fruit flies had a significantly higher survival rate than the control group, with an 8% increase in median survival time.
Figure Note: Survival curves of female fruit flies under starvation (wDah vs. 112b mutant) – showing prolonged survival in the mutant. -
Oxidative stress (abnormal stress caused by "harmful ROS" in other studies): Mutant fruit flies (both male and female) had higher survival rates than the control group. Median survival time increased by 50% in males and 40% in females.
Moreover, regardless of gender, mutant fruit flies had significantly higher expression levels of antioxidant genes than the control group.
Figure Note: Survival curves of male/female fruit flies under oxidative stress (wDah vs. 112b mutant) – showing improved survival in mutants; and antioxidant gene expression (GFP/Actin ratio) – higher in mutants.
2. Regulated Muscle Function
As a "regular resident" of nerve cells, altered DmGluRA expression also subtly affected neuromuscular function in young fruit flies. Mutant flies exhibited stronger climbing ability at a young age.
Figure Note: Muscle function metrics in fruit flies (wDah vs. 112b mutant) – including climbing ability, walking duration, and walking distance across weeks (1/2/3/5) – red for mutants, black for controls, showing better performance in mutants.
Figure Note: Muscle function metrics in fruit flies (wDah vs. 112b mutant) – including climbing ability, walking duration, and walking distance across weeks (1/2/3/5) – red for mutants, black for controls, showing better performance in mutants.
3. No Impact on Reproductive Function
A common trade-off in aging research is that lifespan extension often comes at the cost of reduced reproductive ability. However, DmGluRA breaks this pattern:
After observing unmated female fruit flies and comparing egg production between two groups of females, scientists found that the mutant group still had an 11% lifespan extension without a significant difference in egg count. This indicates that DmGluRA inactivation extends lifespan without sacrificing reproductive capacity.
Figure Note: Left: Survival curve of unmated female fruit flies (wDah vs. 112b mutant) – showing 11% lifespan extension; Right: Egg production comparison – no significant difference between groups.
After observing unmated female fruit flies and comparing egg production between two groups of females, scientists found that the mutant group still had an 11% lifespan extension without a significant difference in egg count. This indicates that DmGluRA inactivation extends lifespan without sacrificing reproductive capacity.
Figure Note: Left: Survival curve of unmated female fruit flies (wDah vs. 112b mutant) – showing 11% lifespan extension; Right: Egg production comparison – no significant difference between groups.
DmGluRA clearly has the potential to be a "longevity gene," but is its effect solely due to neuronal changes regulating the body?
Part 3: The Real Culprit – Ribosomes!
To find out, scientists analyzed gene expression differences between mutant and control fruit flies. They identified 2,271 genes with significant expression changes in mutants: 983 were upregulated, and 1,288 were downregulated.
Figure Note: Volcano plot of differentially expressed genes (FDR < 0.05) – showing log2 fold change (log2FC) vs. significance.
All these differentially expressed genes were enriched in one key process: ribosome biogenesis.
Figure Note: Functional enrichment analysis – top terms include rRNA metabolic process, rRNA processing, ribosome biogenesis, ribonucleoprotein complex biogenesis, etc. (with p-value and gene count metrics).
To confirm this, researchers observed that the nucleoli (which contain rRNA and assemble into ribosomes with proteins) in the intestinal epithelial cells of mutant fruit flies shrank in size. This led to reduced rRNA/gDNA ratios and decreased protein synthesis rates – indicating that DmGluRA deletion delays aging by impairing ribosome biogenesis and protein synthesis.
Furthermore, among the upregulated genes, scientists identified an RNA-binding protein called FMRP (Fragile X Mental Retardation Protein) – which localizes to ribosomes and has an antagonistic relationship with glutamate receptors. FMRP regulates protein translation by binding to polyribosomes and interacting directly with specific mRNA sequences or structures.
Figure Note: FMRP expression levels (FMRP/Actin ratio) – significantly higher in 112b mutants vs. wDah controls.
When FMRP expression was inhibited in mutant fruit flies, the lifespan-extending effect of DmGluRA mutations almost completely disappeared. Additionally, the reduced nucleolar size in the midgut epithelial cells of DmGluRA mutants was closely linked to FMRP expression – nucleolar size returned to normal in double mutants (DmGluRA⁻/⁻; FMRP⁻/⁻).
Figure Note: Left: Survival curve of fruit flies (wDah vs. 112b mutant vs. Fmr[392]; 112b double mutant) – showing loss of lifespan extension when FMRP is inhibited (red dashed line vs. red solid line); Right: Nucleolar size comparison – double mutants recover normal nucleolar size.
The mystery is now solved: from MSG to neurotransmitter receptors, and finally to ribosome inhibition for longevity – the anti-aging pathway is unexpectedly diverse, but two key proteins emerge: DmGluRA and FMRP.
In the normal aging process, DmGluRA activity restricts FMRP expression, relieving FMRP’s inhibition of ribosome biogenesis. When DmGluRA is knocked out or inhibited, FMRP expression increases, which in turn suppresses ribosome biogenesis and extends lifespan.
Unanswered Questions
The study confirms the anti-aging potential of the mGluR signaling pathway – ribosomes (key machines for cellular protein synthesis) are known to have reduced biogenesis as a marker of longevity. Future research may shift focus from the well-studied "SIRT" family of longevity proteins to ribosome-related metabotropic glutamate receptors (mGluRs) to explore their anti-aging potential.
However, the authors note that mechanisms underlying gender differences (e.g., more significant lifespan extension in females) and the specific role of FMRP remain unclear. Thus, this newly identified "longevity gene" still requires further investigation.
References
[1] Guan, C., Otchere, A., Laskovs, M., Papatheodorou, I., & Slack, C. (2025). Genetic and Pharmacological Inhibition of Metabotropic Glutamate Receptor Signalling Extends Lifespan in Drosophila. Aging Cell, e14500. Advance online publication. https://doi.org/10.1111/acel.14500
[2] Mattson, M. P. (2010). Glutamate and neurotrophic factors in neuronal plasticity and disease. Annals of the New York Academy of Sciences, 1144(1), 97-112.
[3] Traynelis, S. F., Wollmuth, L. P., McBain, C. J., Menniti, F. S., Vance, K. M., Ogden, K. K., Hansen, K. B., Yuan, H., Myers, S. J., & Dingledine, R. (2010). Glutamate receptor ion channels: structure, regulation, and function. Pharmacological Reviews, 62(3), 405–496. https://doi.org/10.1124/pr.109.002451
[4] Yin, S., & Niswender, C. M. (2014). Progress toward advanced understanding of metabotropic glutamate receptors: structure, signaling and therapeutic indications. Cellular Signalling, 26(10), 2284–2297. https://doi.org/10.1016/j.cellsig.2014.04.022
[2] Mattson, M. P. (2010). Glutamate and neurotrophic factors in neuronal plasticity and disease. Annals of the New York Academy of Sciences, 1144(1), 97-112.
[3] Traynelis, S. F., Wollmuth, L. P., McBain, C. J., Menniti, F. S., Vance, K. M., Ogden, K. K., Hansen, K. B., Yuan, H., Myers, S. J., & Dingledine, R. (2010). Glutamate receptor ion channels: structure, regulation, and function. Pharmacological Reviews, 62(3), 405–496. https://doi.org/10.1124/pr.109.002451
[4] Yin, S., & Niswender, C. M. (2014). Progress toward advanced understanding of metabotropic glutamate receptors: structure, signaling and therapeutic indications. Cellular Signalling, 26(10), 2284–2297. https://doi.org/10.1016/j.cellsig.2014.04.022