The new study, published in Communications Biology journal by Juhi Kumar, Kristal Ng and Charalampos Rallis, sheds light on how drugs and natural metabolites can influence lifespan through the Target of Rapamycin (TOR) pathway.
TOR is a conserved signalling pathway active in humans as well as yeast. It is a central regulator of growth and ageing fundamental in age-related diseases such as cancer and neurodegeneration and is already a major focus of anti-ageing and cancer research, with drugs such as rapamycin showing promise in extending healthy lifespan in animals.
Rapalink-1, the new drug studied by the team, is a next-generation TOR inhibitor currently under investigation for cancer therapy. The researchers found that rapalink-1 not only slowed aspects of yeast cell growth but also significantly extended lifespan, working through TORC1 - the growth-promoting arm of the TOR pathway.
Unexpectedly, the study revealed a key role for a set of enzymes called agmatinases, which break down the metabolite agmatine into polyamines. These enzymes act as part of a previously unknown "metabolic feedback loop" that keeps TOR activity in check. 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.
"By showing that agmatinases are essential for healthy ageing, 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 ageing."
Rallis acknowledges that agmatine supplements are available in the market, but stresses: "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."
The findings have broad implications for healthy ageing research, cancer biology, and metabolic disease, pointing to new strategies that combine TOR-targeting drugs with dietary or microbial interventions.
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 Sep 29;8(1):1364. doi: 10.1038/s42003-025-08731-3