October 14, 2025 | The Target of Rapamycin (TOR) signaling pathway is a prime target for therapeutic development, since its dysregulation is implicated in promoting aging and a range of age-related diseases. By inhibiting TOR, the prescription medication rapamycin has been successfully used to prevent organ transplant rejection and treat certain cancers, but its use for anti-aging purposes in healthy individuals has yet to be approved by the Food and Drug Administration (FDA).
But a decade from now, FDA-approved healthspan drugs may start becoming more commonplace in the clinic, according to Charalampos Rallis, Ph.D., associate professor in genetics, genomics, and fundamental cell biology, and director of industrial innovation at Queen Mary University of London. His part in the quest is to better describe the malfunctioning TOR pathway, thereby guiding clinical development of disease and anti-aging treatments.
To that end, he and his colleagues recently discovered many TOR-regulated genes and hit on the anti-aging action of enzymes called agmatinases that break down agmatine, a derivative of the amino acid arginine. Agmatinases function in a metabolic circuit controlling protein translation levels and lifespan in fission yeast (Communications Biology, DOI: 10.1038/s42003-025-08731-3). Arginine and agmatine are popular, TOR-activating dietary supplements, especially among athletes and bodybuilders, says Rallis.
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.
The focus in this study was the third-generation TOR inhibitor known as Rapalink-1 that causes cells to enhance the breakdown of arginine, he notes. Rapalink-1 is a chemical compound where the first-generation inhibitor rapamycin is linked with the second-generation inhibitor sapanisertib (MLN0128) to create a more potent and effective molecule.
Through inhibiting TOR, Rapalink-1 causes cells to think that they’re starving, says Rallis. They respond by activating agmatinases, among other genes. Agmatinases are important “not only for normal conditions, but also for pathological conditions like cancer,” he adds.
While the TOR pathway promotes growth, the AMP-activated protein kinase (AMPK) pathway activates stress responses. “TOR and AMPK are the ying and yang of growth and metabolism,” Rallis says. “They antagonize each other, essentially, so when TOR is up, AMPK will be down [and vice versa].”
The take-home message, says Rallis, is that Rapalink-1 can promote lifespan and agmatinases fine-tune TOR activity within cells through a metabolic feedback loop. The research team believes this metabolic control over TOR is conserved from yeast to humans.
Agmatine is produced by diet and gut microbes, he notes. The study may therefore “help explain how nutrition and the microbiome influence aging.”
The next step is to go into human cells, including ones from people with pathological conditions like cancer where TOR is dysregulated, and to see whether targeting agmatinases could potentially inhibit tumor growth and progression, says Rallis.
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