Rapalink-1 reveals novel TOR dependent genes and the role of agmatinases  in growth and lifespan
mTOR is a conserved proaging pathway with characterised inhibitors like rapamycin and torins. A third-generation inhibitor, rapalink-1, has been developed, however, its effects on organismal gene expression and lifespan have not been evaluated. Here, we demonstrate that rapalink-1 affects fission yeast spatial and temporal growth and prolongs chronological lifespan. 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 aging including all fission yeast agmatinases, the enzymes responsible for processing agmatine to putrescine and urea. We identify sensitive and resistant mutants to agmatine and putrescine and show that all fission yeast agmatinase enzymes are required for normal lifespan. Genetic interactome assays for the agmatinase agm1 and further analyses demonstrate that impairing the agmatinergic branch of arginine catabolism results in mTOR activity levels that are beneficial for growth but detrimental for chronological aging. Our study reveals metabolic circuits with possible implications to other systems, including human cells. Overall design: To compare the effects of Rapamycin and Rapalink-1 on gene expression, S.pombe cells were treated with 100nM of Rapamycin and Rapalink-1 for 5 hours, followed by downstream processing to extract RNA and compare transcriptomic profiles between untreated and treated yeast cells.