Rapalink-1 Identified as Promising Anti-Aging Drug Candidate
Researchers uncover how rapalink-1 targets the TOR pathway to extend lifespan – opening new doors for anti-aging therapies.
Researchers from Queen Mary University of London’s School of Biological and Behavioural Sciences have found that the next-generation target of rapamycin (TOR) pathway inhibitor – rapalink-1 – can significantly prolong lifespan in simple fission yeast.
The study, published in Communications Biology, highlights how both drugs and natural metabolites influence aging through the target of rapamycin (TOR) pathway.
TOR pathway: A central regulator of aging
The TOR pathway is a highly conserved signaling mechanism, active in yeast and humans alike. It regulates growth, metabolism and aging, and has been directly implicated in age-related diseases such as cancer and neurodegeneration. Drugs that target this pathway, including the well-studied rapamycin, have already shown promise in extending healthy lifespan in animal models.
Rapalink-1, the focus of the current study, is a next-generation TOR inhibitor originally developed for cancer therapy. The researchers demonstrated that rapalink-1 not only slowed yeast cell growth but also extended lifespan by targeting TORC1, the growth-promoting branch of the TOR pathway.
“Our group has a deep interest in the TOR pathway in both aging and disease,” Dr. Charalampos (Babis) Rallis, associate professor in genetics, genomics and fundamental cell biology and senior author of the study, told Technology Networks. “For many years we have explored pharmacological inhibitors of the pathway – including rapamycin, caffeine and torin1 – using fission yeast. It was a natural continuation to explore rapalink-1 in this context.”
Discovery of a new enzyme class in aging control
The team uncovered a central role for agmatinases – enzymes that break down the metabolite agmatine into polyamines. These enzymes form part of a previously unknown “metabolic feedback loop” that helps regulate TOR activity.
Loss of agmatinase function caused yeast cells to grow more rapidly but age prematurely, revealing a trade-off between short-term growth and long-term survival. Supplementing yeast with agmatine, or its product, putrescine, also promoted longevity under certain 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 Rallis. “Because agmatine is produced by diet and gut microbes, this work may help explain how nutrition and the microbiome influence aging.”
Nutrition, microbiome and caution on supplements
The findings place agmatine at the intersection of diet, gut microbiota and host metabolism, suggesting that nutritional strategies and microbiome-targeted interventions could shape healthy aging.
“Agmatine sits at the intersection of diet, gut microbiota and host metabolism. Strategies that optimize arginine intake and microbiome health could sustain agmatine exposure,” Rallis explained. “This could in turn support healthy brain function, metabolic balance and stress resilience during aging.”
However, he stressed caution when considering dietary supplementation. “We should be cautious about consuming agmatine for growth or longevity purposes. Our data indicate that 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.”
He added: “Our data showcase beneficial effects when [supplemented] in the right amounts. But it can also be detrimental if nitrogen catabolism pathways are impaired. It is good to stress that the data derive from yeast studies. That means that appropriate longitudinal human studies are required.”
Broader implications for aging and disease
The study provides a dual discovery, said Rallis:
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“Firstly, the fact that this part of the arginine catabolism was significantly enhanced in TOR inhibition rather than the branch that produces ornithine,” Rallis noted. “It made sense after we realized the ‘geography’ of these enzymes within the cell and in relation to the vacuole-anchored TOR complex. Second, the elegance of this wiring and how cells try to ensure energy efficiency depending on stress and nutrients.”
The researchers are now investigating whether these mechanisms are conserved in human cells. “It is very likely, given the conservation of TOR complexes and of their connections. We are already looking into this using human neurons and skin cells,” Rallis said.
The findings open up opportunities for new therapeutic strategies combining TOR-targeting drugs with dietary and microbial interventions. These could prove beneficial not only for promoting healthy aging but also for tackling cancer, neurodegeneration and metabolic disease.
Rallis concluded: “Our data highlight how diet, metabolism and cellular pathways are tightly linked. Understanding this interplay is vital if we are to design interventions that extend health span without unintended consequences.”
Reference: Kumar J, Ng K, Rallis C. Rapalink-1 reveals TOR-dependent genes and an agmatinergic axis-based metabolic feedback regulating TOR activity and lifespan in fission yeast. Commun Biol. 2025;8(1):1364. doi: 10.1038/s42003-025-08731-3
About the interviewee
Dr. Charalampos (Babis) Rallis
Following his PhD studies at the MRC National Institute for Medical Research, Babis completed postdoctoral research at the CRUK Lincoln's Inn Fields Laboratories. This was followed by a Research Associate position at the UCL Institute of Healthy Ageing, working on nutrient-responsive pathways, aging mechanisms, quiescence and senescence. Babis moved to the University of Essex in 2020, where he established his own independent research group. He joined Queen Mary University of London in September 2023. The Rallislab (www.rallislab.org) investigates gene and protein networks implicated in cellular fitness and metabolism, neurodegeneration, cancer and aging with a focus on the nutrient-responsive signaling pathway Target of Rapamycin (TOR). The group aims to elucidate the molecular mechanisms and principles behind senescence and lifespan and apply this knowledge for the amelioration, or even prevention, of age-related diseases. In addition, the group performs quantitative fitness profiling of microbial strains, microbiomes and mycobiomes and explore the effects of nutrition on biome physiology and subsequent effects on human healthy aging. The group uses established and relevant cellular systems such as the fission yeast Schizosaccharomyces pombe and mammalian 2D and 3D tissue culture systems, such as fibroblasts, cancer cell lines, human dopaminergic and iPSC-derived motor neurons. Besides classical molecular biology, genetic, cell biology and microscopy approaches, the group utilizes multi-omics (transcriptome, proteome, metabolome and phenome approaches) as well as related data integrations and network biology.
