RapaLink-1

A next-generation drug tested in yeast was found to extend lifespan and slow aging by influencing a major growth-control pathway. Researchers also uncovered an unexpected role for agmatinases, enzymes that help keep this pathway in balance. Diet and gut microbes may affect aging more than expected because they produce the metabolites involved.Researchers at Queen Mary University of London's School of Biological and Behavioural Sciences have demonstrated that the experimental TOR inhibitor rapalink-1 can extend the chronological lifespan of fission yeast, a simple organism widely used to explore basic biological processes. A study published in Communications Biology by Juhi Kumar, Kristal Ng and Charalampos Rallis reports that both pharmaceuticals and naturally occurring metabolites can influence lifespan through the Target of Rapamycin (TOR) pathway. TOR Pathway's Central Role in Growth and Aging The TOR pathway is an evolutionarily conserved signalling system found in organisms ranging from yeast to humans. It plays a vital part in regulating growth and aging and is closely linked to major age-related conditions, including cancer and neurodegenerative diseases. Because of its broad influence, TOR has become a major target in anti-aging and cancer research, with drugs such as rapamycin already showing an ability to extend healthy lifespan in several animal models. Rapalink-1, the compound examined in the investigation, is a next-generation TOR inhibitor currently being studied for potential use in cancer therapy. The research team found that rapalink-1 slowed certain aspects of yeast cell growth while also extending their lifespan. The effect appears to operate through TORC1 -- the growth-promoting component of the TOR pathway. Discovery of a Metabolic Feedback Loop Involving Agmatinases The study unexpectedly identified a significant role for a group of enzymes known as agmatinases, which convert the metabolite agmatine into polyamines. These enzymes appear to participate in a previously unrecognized "metabolic feedback loop" that helps maintain balanced TOR activity. When agmatinase activity was disrupted, yeast cells grew more quickly but showed signs of premature aging, revealing a trade-off between rapid growth and long-term cell survival. The team also found that adding agmatine or putrescine (a related compound) supported longevity in yeast and improved growth under specific conditions. "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," said Dr. Rallis. "Because agmatine is produced by diet and gut microbes, this work may help explain how nutrition and the microbiome influence aging." Caution Around Agmatine Supplementation Rallis noted that agmatine supplements are available commercially but emphasized caution: "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." These findings highlight important connections between TOR signalling, metabolism and longevity. The results may help guide future strategies that pair TOR-targeting drugs with dietary or microbiome-based approaches in the study of healthy aging, cancer biology and metabolic disease.