One and a half times longer
Mammalian enzyme inhibitor extended the life of roundworms by one and a half times
Daria Spasskaya, N+1
American researchers have found that the substance JZL184 from the carbamate class, which was previously known as an inhibitor of mammalian lipase involved in the breakdown of mediators of the endocannabinoid pathway, prolongs the life of roundworms by 45 percent. Despite the fact that worms do not have the same enzyme, scientists have discovered the target of the molecule and have shown that this enzyme performs the same function as in mammals. Thus, not a specific protein was involved in prolonging life, but a whole metabolic pathway, conservative in animals, the authors conclude in an article in Nature Chemical Biology (Chen et al., Pharmacological convergence reveals a lipid pathway that regulates C.elegans lifespan).
In the work, scientists from the Scripps Institute (Discovery of life-extension pathway in worms demonstrates a new way to study aging) investigated small molecules that inhibit the activity of enzymes of the serine hydrolase class, whose representatives had previously been convicted of regulating the lifespan of nematodes Caenorhabditis elegans. These microscopic worms often become a model for life expectancy research, since they normally live only two to three weeks, and genetic engineering methods are well developed for them. In the experiment, various components from the library of hydrolase inhibitors were added to the nutrient medium where nematodes lived and the life expectancy of animals was observed.
Of the 95 substances, only a few components extended the life of worms by about 15 percent, but the most significant result was shown by a substance called JZL184, which increased the lifespan of nematodes by 45 percent. This component was discovered as an inhibitor of mammalian monoacylglycerol lipase (MAGL), which contributes mainly to the destruction of the endocannabinoid 2-AG, which is present in large quantities in the central nervous system. Caenorhabditis elegans does not have the MAGL enzyme, but there is an endocannabinoid system.
The scheme of the screening experiment (above) and the result of the component library study (below). According to the ordinate scale, the change in the life expectancy of animals as a percentage is postponed. R isunok from an article in Nature Chemical Biology.
Using mass spectrometry, the researchers found out that the main target of JZL184 in the body of worms is the hydrolase of fatty acids FAAH-4. Despite the lack of structural similarity with MAGL, it turned out that this enzyme performs the same function, that is, hydrolysis of 2-AG, and JZL184 suppresses this activity. Interestingly, an inhibitor of the related enzyme FAAH-1, which is involved in the degradation of another endocannabinoid, anandamide, and is present in both mammals and worms, did not increase the lifespan of nematodes.
To confirm the participation of FAAH-4 in the lifespan of worms, the authors of the work made genetically modified nematodes without the gene encoding the enzyme. It turned out that the FAAH-4 mutant nematodes actually live longer, probably due to increased resistance to oxidative stress. The accumulation of monoacylglycerides, including 2-AG, was observed in their body. Interestingly, unlike worms watered with an inhibitor, mutant worms had an increased appetite. Since calorie restriction is also a factor in prolonging life, scientists have suggested that increased appetite develops as a compensatory mechanism for increasing life expectancy.
The authors conclude that lipid metabolism, in particular, in the endocannabinoid system, should be studied in more detail in the context of the contribution to both the aging of the body as a whole and to the aging of the brain. So far, the more well-known mechanism associated with aging is autophagy. Recently we told that a component from the ashitaba plant used in oriental medicine, due to the activation of autophagy in cells, increased the life of invertebrates by 20 percent, and partially protected mice from heart attack.
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