Rapalink-1 reveals novel mTOR-dependent genes and an agmatinergic axis-based metabolic feedback regulating mTOR activity and lifespan

The mechanistic Target of Rapamycin, mTOR, is a conserved pro-ageing pathway with characterised inhibitors such as rapamycin, rapalogues and torins. Bi-steric third-generation inhibitors, such as rapalink-1 have been developed, however, their effects on organismal gene expression and lifespan have not been characterised. Here, we demonstrate that rapalink-1 affects fission yeast spatial and temporal growth and prolongs chronological lifespan with a distinct TORC1 selectivity profile. Endosome and vesicle-mediated transport and homeostasis processes related to autophagy and Pik3, the orthologue of human PI3K, render cells resistant to rapalink-1. Our study reveals mTOR-regulated genes with unknown roles in ageing including all fission yeast agmatinases, the enzymes that convert agmatine to putrescine and urea. Through genome-wide screens, we identify sensitive and resistant mutants to agmatine and putrescine. Genetic interactome assays for the agmatinase agm1 and further cell and molecular analyses, demonstrate that impairing the agmatinergic branch of arginine catabolism results in mTOR activity levels that are beneficial for growth but detrimental for chronological ageing. Our study reveals the anti-ageing action of agmatinases within a metabolic feedback circuit regulating mTOR activity levels and ageing and with possible implications to other systems, including human cells.