This study reveals the phenomenon of hyperactivated glutamine metabolism (hyperglutaminolysis) in senescent cells and systematically elucidates a novel molecular mechanism by which sustained mTORC1 activation through arginine biosynthesis promotes cellular and organismal aging, providing new therapeutic targets for interventions against aging and age-related diseases.
Literature Overview
The article “Hyperglutaminolysis drives senescence and aging through arginine-mTORC1 axis activation,” published in Signal Transduction and Targeted Therapy, reviews and summarizes the critical role of glutamine metabolism in cellular senescence and organismal aging. Using multiple senescence models and metabolomic analyses, the study finds that glutaminolysis is significantly enhanced in senescent cells and aged animals—a phenomenon termed “hyperglutaminolysis.” It further reveals that this process promotes arginine biosynthesis, leading to sustained activation of the mTORC1 signaling pathway and thereby driving aging. By integrating cell and animal models, and employing gene knockdown, metabolic intervention, and pharmacological inhibition, the study systematically validates the roles of key enzymes such as GLS1 and ASL in this pathway. This work not only establishes dysregulated glutamine metabolism as a key driver of aging but also defines a novel “glutaminolysis–arginine biosynthesis–mTORC1” signaling axis, offering crucial theoretical insights into the relationship between metabolic reprogramming and aging. The findings significantly expand our understanding of the link between glutaminolysis and aging, holding substantial value for identifying new intervention targets to delay aging and treat age-related diseases.Background Knowledge
Cellular senescence is a core hallmark of organismal aging, and its accumulation is closely associated with various age-related diseases. In recent years, metabolic reprogramming has emerged as a key feature of aging, with alterations in glucose and lipid metabolism being extensively studied. However, the role of amino acid metabolism, particularly glutamine (Gln) metabolism, in aging remains poorly understood. Glutamine is the most abundant free amino acid in the body, and its breakdown begins with glutaminase (GLS), which catalyzes the conversion of glutamine into glutamate and ammonia—a process known as glutaminolysis—that plays essential roles in energy production, antioxidant defense, and biosynthesis. Previous studies have mainly highlighted the antioxidant and potential anti-aging effects of glutaminolysis; however, growing evidence shows that glutaminolytic flux is paradoxically enhanced in aged tissues, suggesting a pro-aging function. The mTORC1 signaling pathway is a central regulator of cell growth, metabolism, and aging, and its aberrant, persistent activation is a hallmark of senescence. Arginine, as an activating amino acid for mTORC1, is sensed by the CASTOR1 protein, which regulates mTORC1 activity. However, the sources of arginine and how its levels are regulated during aging remain unclear. This study elegantly links the products of glutaminolysis (glutamate and ammonia) to the arginine biosynthesis pathway, proposing a novel hypothesis: hyperglutaminolysis may drive aging by increasing arginine supply and consequently activating mTORC1. This conceptual advance is both innovative and translationally significant, aiming to uncover deeper molecular mechanisms by which metabolic dysregulation promotes aging and offering new strategies for developing metabolism-targeted anti-aging therapies.
Research Methods and Experiments
The study first performed metabolomic analyses on three distinct senescence cell models (oxidative stress-induced and replicative senescence), revealing significant metabolic reprogramming of amino acids in senescent cells, with glutamine positioned at the center of the metabolic network. Subsequently, researchers validated that the expression and activity of GLS1, the key enzyme in glutaminolysis, were significantly elevated in various senescent cell types, aged fruit flies, and mouse models, defining “hyperglutaminolysis” as a metabolic hallmark of aging. To investigate its functional role, three strategies were employed to inhibit glutaminolysis: culturing cells in low-glutamine medium, treatment with GLS inhibitors (DON, CB-839), and GLS1 gene knockdown. In cellular models, these interventions significantly reduced the proportion of senescence-associated β-galactosidase (SA-β-gal) positive cells and p16 expression, and suppressed the expression of senescence-associated secretory phenotype (SASP) factors. In fruit fly models, GLS knockdown or inhibitor treatment significantly extended both median and maximum lifespan, and improved locomotor capacity and intestinal barrier integrity.
Further investigation revealed that hyperglutaminolysis leads to aberrant mTORC1 activation, as evidenced by increased phosphorylation of p70/S6K and 4EBP1. Inhibiting glutaminolysis effectively reduced mTORC1 activity and restored autophagic flux. A subsequent round of metabolomic analysis showed that arginine and its precursors (aspartate, citrulline) were elevated in senescent cells and aged fruit flies, and this increase was dependent on glutaminolysis. Supplementing these metabolites restored mTORC1 activity suppressed by glutaminolysis inhibition, whereas knocking down key enzymes in arginine biosynthesis (e.g., ASL) inhibited mTORC1 activation. In aged mice, AAV-mediated knockdown of Asl effectively reduced arginine levels and mTORC1 activity in muscle tissue. Finally, the study confirmed that the arginine sensor CASTOR1 mediates glutaminolysis-induced mTORC1 activation: CASTOR1 knockdown blocked the beneficial effects of glutaminolysis inhibitors on mTORC1 and autophagy, while CASTOR1 overexpression suppressed glutamine-induced mTORC1 activation.Key Conclusions and Perspectives
Research Significance and Prospects
This study challenges the traditional view that glutaminolysis solely exerts antioxidant and anti-aging effects, revealing its “double-edged sword” nature in aging: abnormal enhancement of metabolic flux can paradoxically promote aging. This finding emphasizes the importance of maintaining metabolic homeostasis, rather than simply supplementing or inhibiting specific metabolites, in aging interventions. The newly identified “glutaminolysis–arginine biosynthesis–mTORC1” axis provides a clear molecular link explaining how metabolic reprogramming directly drives aging, particularly by connecting nitrogen metabolism (ammonia) with a core aging pathway (mTORC1), representing a significant theoretical innovation.
From a translational medicine perspective, this study points toward new anti-aging strategies. Targeting key enzymes such as GLS1 or ASL, or modulating the arginine–CASTOR1 signaling axis, may offer potential approaches to delay aging and treat age-related diseases. However, glutamine and arginine play vital roles in numerous physiological processes, and systemic inhibition may lead to side effects. Future research should develop tissue-specific or conditional intervention strategies. Moreover, the study primarily validates the findings in rodent and insect models; further exploration in human aging is needed. Future studies could analyze tissue samples from individuals across different age groups to examine activity changes in this pathway and evaluate its potential as a biomarker of aging.
Conclusion
This study systematically elucidates the central role and molecular mechanism of hyperglutaminolysis in driving cellular senescence and organismal aging. It demonstrates that aberrantly enhanced glutamine metabolism in senescent cells increases the supply of glutamate and ammonia, thereby promoting arginine biosynthesis. Elevated arginine is sensed by the CASTOR1 protein, leading to abnormal and sustained activation of the mTORC1 signaling pathway, which in turn suppresses autophagy and ultimately promotes the establishment and maintenance of senescent phenotypes. This mechanism has been validated across multiple models, including fruit flies and mice, indicating evolutionary conservation. Using genetic and pharmacological interventions, the study shows that inhibiting glutaminolysis or arginine biosynthesis effectively alleviates cellular senescence and extends lifespan in fruit flies. This work not only uncovers a novel link between amino acid metabolic dysregulation and aging but, more importantly, defines a previously unknown signaling axis from glutaminolysis to mTORC1 activation, providing a crucial theoretical framework for understanding the metabolic basis of aging. The findings underscore the critical role of metabolic homeostasis in healthy aging and offer a solid scientific foundation and multiple potential drug targets for developing anti-aging interventions targeting the glutamine–arginine–mTORC1 axis, with profound implications for advancing research on aging and related diseases.
