Hyperglutaminolysis drives senescence and aging through arginine-mTORC1 axis activation.

Abstract

The catabolism of glutamine is essential for living organisms, so that its first step, driven by glutaminase 1 (GLS1), generally referred to as glutaminolysis, plays important roles in physiological metabolism. However, the status and impact of glutaminolysis in pathological contexts such as aging and age-related diseases remain elusive. In this study, through metabolomics analysis and different aging models, we verified the hyperactivation status of glutaminolysis in senescent cells and aged Drosophila and mice, which we term "hyperglutaminolysis". We further confirmed the aging-promoting role of this hyperglutaminolysis by addition and removal intervention experiments. Intriguingly, a novel signaling axis connecting to senescence-associated persistent mTORC1 activation was found. This pathway begins with glutaminase-catalyzed production of ammonium and glutamate, which drives arginine biosynthesis and is subsequently sensed by CASTOR1, leading to persistent mTORC1 activation. The regulatory roles of two key enzymes within this cascade, GLS1 and argininosuccinate lyase (ASL), were specifically investigated and verified by cellular and in vivo experiments, including those using stress-promoted and naturally aged animals, combined with GLS1 and ASL knockdown, and multiple rounds of metabolite analysis. In conclusion, our work positions dysregulated glutaminolysis as a key driver of aging and delineates a previously unrecognized molecular cascade that directly links glutaminolysis, arginine biosynthesis, and mTORC1 activation. These findings significantly expand our understanding of the relationship between glutamine catabolism and aging and are valuable for identifying novel intervention targets aimed at mitigating aging-related processes.