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.
Senior and corresponding author Rallis, together with first author Juhi Kumar, PhD, and Kristal Ng, PhD, reported on their findings in Communications Biology, in a paper titled “Rapalink-1 reveals TOR-dependent genes and an agmatinergic axis-based metabolic feedback regulating TOR activity and lifespan in fission yeast.” In their paper, the team concluded, “Our study reveals the anti-aging action of agmatinases within a metabolic circuit that regulates TOR activity, protein translation levels, and lifespan.”
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.
The researchers set out to investigate the effects of rapalink-1, through comparisons with rapamycin, using fission yeast, a relevant model in cell biology and aging studies. Their results found that rapalink-1 not only slowed aspects of yeast cell growth but also significantly extended lifespan, working through TORC1—the growth-promoting arm of the TOR pathway.
Unexpectedly, the study revealed a key role for a set of enzymes called agmatinases, which break down the metabolite agmatine into polyamines. These enzymes act as part of a previously unknown “metabolic feedback loop” that keeps TOR activity in check. “Using a combination of classical cell biology and genome-wide cell-based screens, we uncover new TOR-related genes and demonstrate that the enzymes converting agmatine to urea and the polyamine putrescine (agmatinases) are a pivotal pathway that positively impacts lifespan,” the team reported.
When agmatinase function was lost, cells grew faster but aged prematurely—highlighting a trade-off between short-term growth and long-term survival. Supplementing yeast with agmatine or putrescine, the compounds linked to this pathway, also promoted longevity and benefited cells under certain conditions. “Microbiota-derived agmatine has been previously reported to prolong host lifespan due to changes in lipid homeostasis,” they continued. “However, here, and for the first time, we reveal that the function of enzymes breaking down agmatine is linked to aging … Our results show that rapalink-1 primarily targets TORC1, prolongs chronological lifespan and demonstrate that TOR activity negatively regulates agmatinase genes,” the authors noted.
Rallis continued, “By showing that agmatinases are essential for healthy aging, we’ve uncovered a new layer of metabolic control over TOR—one that may be conserved in humans. Because agmatine is produced by diet and gut microbes, this work may help explain how nutrition and the microbiome influence aging.”
“Interest in agmatine as a nutraceutical is significant, and it is reported as a promising therapeutic agent for treating a broad spectrum of central nervous system diseases,” the authors noted in their paper. Rallis acknowledged that agmatine supplements are available in the market, but stressed, “We should be cautious about consuming agmatine for growth or longevity purposes. Our data indicate the agmatine supplementation can be beneficial for growth only when certain metabolic pathways related to arginine breakdown are intact. In addition, agmatine does not always promote beneficial effects as it can contribute to certain pathologies.”
The study findings have broad implications for healthy aging research, cancer biology, and metabolic disease, pointing to new strategies that combine TOR-targeting drugs with dietary or microbial interventions. In their report, the authors concluded, “Understanding how TORC1 activity is tuned may be beneficial in both normal ageing and also pathological states as well as in cancer where TOR plays important roles.”
