New drug Rapalink-1 slows cellular aging, study finds

A recent study conducted by researchers at Queen Mary University of London unveiled a new mechanism through which cells control aging. With simple fission yeast, the scientists showed that Rapalink-1, a drug already in clinical trials as a potential anti-cancer agent, induces longevity through the creation of a feedback loop within cellular metabolism. The research opens new perspectives on the possibility of elucidating how drugs, food, and gut microbes can influence longevity.

At the heart of this study is the Target of Rapamycin, or TOR, a master kinase of cell growth, metabolism, and aging. The pathway is present in nearly all living organisms, from yeast to humans. TOR functions through two primary complexes—TORC1, which is pro-cell growth and protein synthesis, and TORC2, which maintains cell viability and shape. Hyperactive TORC1 has been linked to cancer, metabolic illness, and aging diseases.

Rapamycin, a widely used TORC1 inhibitor, has been shown for decades to lengthen lifespan in yeast, worms, flies, and mice. A newer and more specific drug derivative is rapalink-1. It pairs the activity of rapamycin with a second drug that competes with ATP, creating a bi-steric molecule that more specifically targets TORC1.

To see the effect of Rapalink-1 on aging, scientists treated yeast cells with the drug and compared their growth and gene expression with rapamycin-treated cells. They noted how the cells grew, how big they grew before they divided, and how long they lived after they ceased to grow.

Both rapamycin and Rapalink-1 suppressed cell growth and induced yeast to divide at smaller sizes. Rapalink-1, however, left one distinguishing signature: instead of shutting off cell division quickly, it instilled a more subtle, long-term deviation from growth. It also extended yeast cells' stationary-phase survival nearly as much as rapamycin, guaranteeing that its effect is largely via TORC1.

At the molecular level, Rapalink-1 halved protein manufacture and made modifications to instruct the cell to conserve energy. One of them, designated as Gaf1, which would normally roam the cell freely, migrated straight into the nucleus when treated—one of the classic signs of TORC1 inhibition. These modifications indicate that the drug is effectively flipping the switch on the growth-stimulating activity of TOR so that the cell can focus on repair and maintenance.

To find out which genes made or sensitized the cells to the drug, the scientists gave Rapalink-1 to mutants of yeast in the thousands and observed them growing. Cells that grew poorly when the drug was present tended to lack genes for protein synthesis or mitochondrial function. Cells that grew better had mutations with autophagy, recycling, or nutrient sensing—both processes that cells need during stressful conditions.

A more detailed examination of gene expression showed Rapalink-1 caused much more global changes compared to rapamycin. Nearly 200 genes enhanced their activity, many of which are related to vacuole transport, small molecule metabolism, and transmembrane transport. Four ribosome assembly and tRNA metabolism genes were dramatically turned off. More than 500 genes were modulated in a novel fashion by Rapalink-1, demonstrating Rapalink-1 targets other biological pathways besides those targeted by rapamycin.

There was a surprise twist: Rapalink-1 significantly activated the expression of three agmatinase genes—agm1, agm2, and agm3—enzymes that degrade agmatine to putrescine, both of which are part of arginine metabolism. The discovery hinted at the possibility that these enzymes could have a newly discovered function in regulating lifespan.

To probe this hypothesis, researchers knocked out the individual agmatinase genes in yeast. All the mutants lived shorter than normal cells, and those with fewer than two agmatinase genes aged even faster. Rapalink-1 still lengthened their lifespans, albeit less so in some cases.

The researchers then added either agmatine or putrescine to yeast directly. Surprisingly, each molecule separately extended longevity, suggesting that the metabolites help the cell maintain low levels of TORC1. Cells treated with either substance lived for a substantially longer period, in keeping with the hypothesis that arginine degradation, via the so-called "agmatinergic axis," gets channeled into the same longevity pathway modulated by Rapalink-1.

Further genetic mapping revealed how this system is integrated into the TOR network. Cells that did not have agmatinase genes had more active TORC1, were larger, and produced more of the proteins involved in quick growth. They also had fewer stress signals, which kept their metabolism in "growth mode." But when agmatinase enzymes existed and were active, they acted as brakes, restraining TORC1 activity.

The researchers reasoned that when TORC1 is inhibited—either due to nutrient starvation or drug treatment—cells step up agmatinase activity to recycle arginine. It does so in order to produce compounds that keep cells in the low-growth, high-survival state that promotes longevity.

Lead author Dr. Charalampos Rallis and his team noted that these findings might reach far beyond yeast. TOR, arginine metabolism, and polyamines exist across nearly all species, including humans. “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.

Since agmatine is present in food and also generated by gut bacteria, the research may also tell us more about the role of diet and the microbiome in aging. Agmatine supplements are already available, although Dr. Rallis is cautioning against taking it. "We need to be cautious about using agmatine for growth or longevity," he said. "Our results suggest that the therapeutic effects of agmatine depend on the operation of the body's arginine pathways in a context-dependent manner." In some cases, it actually causes certain diseases."

The study suggests balance among metabolism, cellular stress, and lifespan. Excessive TORC1 expands but cuts life. Insufficient levels, and cells can't have minimal functions. Agmatinergic feedback system appears to hold the balance.

This discovery has the potential to transform how researchers approach aging and disease. Rapalink-1 presents a less extreme tool with which to delineate TORC1's activity, enabling researchers to identify genes and metabolites that regulate aging with greater specificity than with drugs like rapamycin in the past.

Since TORC1 is such a dominant player in cancer, diabetes, and neurodegenerative disease, the study points toward new treatments that pair TOR-targeting drugs with nutritional or microbiome-based therapies.

And if the same networks dominate in humans, agmatine level control—through diet, gut health, or drugs—could one day contribute to healthy aging and metabolic health.

In the meantime, yeast is a powerful model, with even the most basic organisms having sophisticated secrets to reveal about how life maintains itself.

Research findings are available online in the journal Communications Biology.

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