A new study published in Frontiers of Pharmacology has shown that glutamine deprivation might speed up aging while glutamine supplementation reduces oxidative stress-induced senescence in mice [1].
Glutamine is an amino acid of paramount importance for many cellular functions. It is involved in the synthesis of various crucial molecules, such as the neurotransmitter glutamate and the energy molecule ATP. Recently, there has been an increased interest in the link between glutamine metabolism and aging.
Glutamine-glutamate levels are reduced in the brains of patients with Alzheimer’s disease [2], although studies examining this difference between Alzheimer’s patients and healthy controls have shown controversial results [3]. Nevertheless, therapeutic approaches aimed at restoring the imbalance between the glutamate (excitatory) and GABA (inhibitory) systems observed in Alzheimer’s disease are already being investigated in clinical trials.
Glutamine deprivation has been shown to stimulate senescence, while glutamate supplementation has demonstrated a neuroprotective effect in mouse models of some neurodegenerative diseases [4].
Glutamine was also shown to be vital for the regulation of mTOR, thus involved in autophagy, which plays a critical role in the context of aging. However, the exact role that glutamine plays in autophagy is unknown.
In this study, the researchers sought to investigate the role that glutamine plays in senescence and aging by uncovering the pathways activated by glutamine deprivation. They also explored if glutamine supplementation would be beneficial in a mouse model of accelerated aging.
First clues
In their first series of experiments, the researchers examined the effects of glutamine deprivation in vitro. They placed two cell lines in either glutamine-containing (control) or glutamine-free (experimental) mediums. Glutamine deprivation resulted in increased cell death, reduced cell proliferation, and induced expression of senescence-associated genes.
The researchers then exposed fruit flies to a glutamine-deficient diet to check if they could get similar results in vivo. Indeed, flies following the diet had a reduced lifespan and an increased level of senescence, as evidenced by accumulation of the senescence marker SA-β-gal in the gut.
Getting deeper
Next, the researchers assessed how glutamine deprivation affects autophagy using cell cultures. They showed that a glutamine-free medium impaired autophagy via activation of mTOR and disrupted lysosomal function, as evidenced by p62 accumulation and reduced expression of the autolysosomal gene TFEB and its targets, respectively, particularly in the long term.
Meanwhile, inhibiting mTOR signaling with either rapamycin or the PI3K/Akt inhibitor LY294002 mitigated the autophagy impairment and senescence in glutamine-deprived cells. Therefore, this set of experiments confirmed that low glutamine levels inhibit autophagy by activating mTOR and inducing senescence.
Aging context
In the final set of experiments, the researchers explored if glutamine supplementation could fight senescence induced by oxidative stress. First, they exposed a cell culture to hydrogen peroxide (H2O2) to induce oxidative stress. Glutamine supplementation, as expected, reduced senescence in this model.
Then, the scientists used a senescence-induced progeric mouse model to assess the effect of glutamine supplementation in vivo. In this case, D-galactose-treated mice were used as a model of accelerated aging caused by an increased oxidative stress. The mice were given 3% glutamine in drinking water for two months. As a result, the mice in the glutamine supplementation group showed improved hair gloss and density, restored muscle strength, reduced senescence, and increased autophagy compared to control D-galactose mice.
Abstract
Glutamine is a conditionally essential amino acid involved in energy production and redox homeostasis. Aging is commonly characterized by energy generation reduction and redox homeostasis dysfunction. Various aging-related diseases have been reported to be accompanied by glutamine exhaustion. Glutamine supplementation has been used as a nutritional therapy for patients and the elderly, although the mechanism by which glutamine availability affects aging remains elusive. Here, we show that chronic glutamine deprivation induces senescence in fibroblasts and aging in Drosophila melanogaster, while glutamine supplementation protects against oxidative stress-induced cellular senescence and rescues the D-galactose-prompted progeria phenotype in mice. Intriguingly, we found that long-term glutamine deprivation activates the Akt-mTOR pathway, together with the suppression of autolysosome function. However, the inhibition of the Akt-mTOR pathway effectively rescued the autophagy impairment and cellular senescence caused by glutamine deprivation. Collectively, our study demonstrates a novel interplay between glutamine availability and the aging process. Mechanistically, long-term glutamine deprivation could evoke mammalian target of rapamycin (mTOR) pathway activation and autophagy impairment. These findings provide new insights into the connection between glutamine availability and the aging process.
Conclusion
Although this study mostly explored the effect of glutamine deprivation in cell cultures and fruit flies, it provides some mechanistic insights regarding the role of glutamine in aging. Low levels of glutamine might impair autophagy via activating mTOR signaling, while glutamine supplementation could be a potential therapeutic approach for age-associated pathologies characterized by reduced levels of glutamine. This certainly requires additional research, especially to understand why glutamine levels go down in the first place.
Literature
[1] Zhou, J. et al. Glutamine Availability Regulates the Development of Aging Mediated by mTOR Signaling and Autophagy. Front. Pharmacol. 13, 924081 (2022).
[2] Huang, D. et al. Glutamate-glutamine and GABA in brain of normal aged and patients with cognitive impairment. Eur. Radiol. 27, 2698–2705 (2017).
[3] Madeira, C. et al. Elevated Glutamate and Glutamine Levels in the Cerebrospinal Fluid of Patients With Probable Alzheimer’s Disease and Depression. Front. Psychiatry 9, 561 (2018).
[4] Chen, J. et al. The impact of glutamine supplementation on the symptoms of ataxia-telangiectasia: a preclinical assessment. Mol. Neurodegener. 11, 60 (2016).
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