Gemfibrozil reduced frailty in old mice: the authors linked the effect to dietary peptide transport
Gemfibrozil reduced frailty in old mice: the authors linked the effect to dietary peptide transport
The triglyceride-lowering drug extended lifespan in yeast and nematodes. In 20-month-old female mice, it reduced the overall frailty index over eight months. The authors traced a sequence from short peptide transport to mTOR signaling.
Gemfibrozil has been used to treat high triglycerides since 1976. In a paper published on August 15, researchers tested whether restricting the intestinal uptake of amino acids could affect aging in model organisms.
Digestion breaks proteins down into individual amino acids and dipeptides and tripeptides, which are short chains of two or three amino acids. PEPT1 is a transporter protein on the surface of small-intestinal cells. It carries these chains into the cells, where they are broken down and added to the amino acid pool. Amino acid availability influences the activity of mTOR, a cellular signaling system that promotes protein synthesis and growth.
The study builds on earlier work. In a 2014 study, five coauthors of the current paper examined ibuprofen in yeast. The drug reduced tryptophan uptake, while deletion of the tryptophan transporter extended the cell's replicative lifespan. The new study broadens this line of research from the transport of one amino acid in yeast to the transport of short peptides in several organisms and its connection to mTOR.
The authors first tested the usual target of fibrates, PPAR-α, a protein that regulates lipid metabolism. Gemfibrozil still extended lifespan in yeast lacking candidate PPAR-α analogues. Fenofibrate and clofibrate had no such effect in the same experiments. In 23 of 27 growth media in which gemfibrozil prevented yeast from using the available nitrogen source, that source consisted of dipeptides. This result directed the researchers toward peptide transporters.
Gemfibrozil reduced the uptake of a fluorescently labeled dipeptide in yeast, nematodes, human cells, and isolated segments of mouse intestine. Removing the transporters in yeast or suppressing them in nematodes extended lifespan, and gemfibrozil produced no additional effect. In human cells lacking PEPT1, gemfibrozil also no longer reduced measures of mTOR activity. A dipeptide mixture activated mTOR, and gemfibrozil blocked this effect, while signaling induced by free amino acids remained intact.
After eight months of gemfibrozil-supplemented food, the total score on a 30-item frailty index decreased by 35% at the low dose and by 45% at the high dose in 20-month-old female mice. This index combines several age-related features, including grip strength and hearing, into a single measure. The authors interpreted the findings as one sequence: peptide transport → amino acid availability → mTOR → age-related features in old mice.