TOR Inhibitors Could One Day Be Multi-Purpose Healthspan Drugs

By Deborah Borfitz 

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. 

Dysregulated TOR 

Rallis says his group is interested in looking into how nutrients interact with genes and proteins within cells and to understand the effects on cellular fitness and healthspan when cells encounter any kind of stress. Cells realize nutrients via nutrient response proteins, typically kinases that operate within signaling pathways—notably, TOR—to prompt a “burst of energy” that is evolutionarily conserved from yeast to humans over 500 million years. 

When activated, the TOR kinase pathway instructs proliferative cells, such as those on the skin and in the gut, to grow in terms of volume but also in time, he continues. “It’s the core of our growth, but ... when things go bad with this pathway it can go really bad.” Dysregulated TOR is implicated in more than three-quarters of cancers. 

It has also been known for a few decades now that super-active TOR in cells or model organisms can be detrimental, says Rallis, which is why it has been termed a pro-aging pathway. “It boosts the aging phenotypes.” 

TOR-inhibiting rapamycin was discovered in 1964 in soil samples from Easter Island, named Rapa Nui by its indigenous people. The bacteria producing the antibiotic and immunosuppressant compound were isolated from these samples. 

Reading Food 

Fission yeast used in the latest study is an excellent model for cancer research, says Rallis. “We call it mini-mammal because the structure of its chromosomes and the proteins or circuits that control its cell cycle are very similar to human cells.” 

This highlights the relevance of TOR’s nutrient-reading abilities; when a lot of protein is consumed, the signaling pathway is activated. One of the mechanisms of its activation involves arginine found in the lysosomes of cells, he says. Lysosomes are little sacs serving as the cellular digestive system that takes up amino acids and, since a part of the cell’s TOR is lysosomal surface, it will “sense” arginine and instruct the cell to grow. 

When agmatinases are very active, they’ll participate in breaking down arginine as needed—when cells are starving and TOR is downregulated, he offers an example, and the cell needs to keep it low. 

In addition, low TOR allows the activation of autophagy (the cell’s recycling system). In this way, cells “recycle materials more efficiently,” says Rallis. These “scavenging mechanisms,” biologically speaking, “boost our stress resilience because beyond recycling valuable nutrients, they also remove damaged cell parts.” 

Moreover, when cells break down arginine to agmatine they produce other chemicals such as putrescine and spermidine. These are known polyamines, Rallis says, protective molecules that can function as antioxidants and promote autophagy.  

Two TORCs 

The TOR kinase is found in two functionally and structurally distinct protein complexes known as TOR complex 1 (TORC1) and TOR complex 2 (TORC2). While Rapalink-1 can suppress both complexes, in the concentrations and timeframes used in the latest study, it showed a selectivity for TORC1. 

TORC1is the growth-promoting arm of the TOR pathway responsible for its association with aging. TORC2, in contrast, has to date been “more implicated in ... the spatial organization of cells, some aspects of how the genes are organized within the nucleus, and with the cell’s survival,” says Rallis. 

“Rapamycin works preferentially on TORC1 and for prolonged periods of exposure in very high amounts it will also start hitting TORC2,” he continues. Second-generation inhibitors, including torin1, will constrain both TORC1 and TORC2 complexes by blocking the ATP-binding site of TOR and is under clinical trials for various cancers. ATP (adenosine triphosphate) is the main energy currency of cells. 

Promising Possibilities 

The Rallis lab already knows that Rapalink-1 and torin1 could be clinically valuable based on experiments it has conducted on human cells, although the results have yet to be published.  

“We already have the first indications through assays simulating pathological conditions that these drugs can be beneficial for age-related disease,” he says. 

In other lab studies involving human cancer cells, including those arising in the gut, the team also witnessed “clear effects of these TOR inhibitors,” says Rallis. The cells showcase gene expression signatures very much like those observed in yeast when treated with the same inhibitors. 

The plan is to collaborate with other groups who will do similar experiments with Rapalink-1 and torin1 using human organoids and small animal models. Rallis predicts that a strong body of evidence will emerge over the next years, although clinical trials will be needed to establish the benefits in humans.   

The Fight 

For anyone considering or currently using widely available agmatine supplements, Rallis advises caution. Supplementation may confer beneficial fitness-related effects, but, as the latest study shows, on the condition that the pathways that recycle amino acids and nitrogen are intact. 

In addition, agmatine is a promising compound for the treatment of central nervous system-associated diseases. It is a natural metabolite, a large portion of which in the human body is supplemented by food intake and the gut microbiota, he says. Long-term (i.e., five-year) supplementation studies have demonstrated its safety in the analyzed doses. Nevertheless, agmatine does not always promote beneficial effects as it can contribute to pathology. 

“Aging research is very active and ... we are now at the crossroads of going more and more into human studies,” Rallis points out. Biogerontologists like himself “don’t want to make people live forever; the main thing we are looking at is healthspan and to push back age-related diseases.” 

The human population is living longer thanks to current medicines, so more people are around long enough to experience neurodegeneration, cardiovascular problems, and metabolic syndromes. “This is what we want to fight.”