Note that this is a preprint.
It has not yet been peer reviewed by a journal.
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Abstract
mTOR is a conserved pro-ageing pathway with characterised inhibitors such as rapamycin, rapalogues 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 ageing 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 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 metabolic feedback circuits with possible implications to other systems, including human cells.
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Such inventions and studies regarding new generation rapalogs are good developments. The fact that even IL-11 inhibition delays aging through mTOR reveals how important the mtor pathway is in biological aging. Probably the most accepted theory of cellular aging in the future will be the hyperfunctional theory of aging.
Anti-Aging Enzyme Class Revealed by New TOR Inhibitor
Researchers at Queen Mary University of London’s School of Biological and Behavioural Sciences, using the simple fission yeast as a model, have shown that a new target of rapamycin (TOR) inhibitor, rapalink-1, which is in development against cancer, prolongs chronological lifespan.
The study, headed by Charalampos Rallis, PhD, revealed TOR-regulated genes with unknown roles in aging, and could shed new light on how drugs and natural metabolites can influence lifespan through the TOR pathway.
TOR is a conserved signaling pathway that is active in humans as well as in yeast. It is a central regulator of growth and aging, fundamental in age-related diseases such as cancer and neurodegeneration. The pathway is already a major focus of anti-aging and cancer research, with drugs such as rapamycin showing promise in extending healthy lifespan in animals. “Pharmacological inhibition of the evolutionarily conserved, nutrient-responsive and pro-aging target of rapamycin signaling pathway presents great interest in disease and biogerontology,” the authors wrote.
Rapalink-1, the new drug studied by the team, is a next-generation TOR inhibitor currently under investigation for cancer therapy. “Bi-steric third-generation inhibitors, such as rapalink-1 have been developed; however, their effects on organismal gene expression and lifespan have not been characterized,” they pointed out.
Rapalink-1 reveals TOR-dependent genes and an agmatinergic axis-based metabolic feedback regulating TOR activity and lifespan in fission yeast
The Target of Rapamycin, TOR, is a conserved signalling pathway with characterised chemical inhibitors such as rapamycin and torin1. 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 render cells resistant to rapalink-1. Our study reveals TOR-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 TOR activity levels that are beneficial for growth but detrimental for chronological ageing. Our study reveals the anti-ageing action of agmatinases within a metabolic circuit that regulates TOR activity, protein translation levels and lifespan.