An alcohol-breaking enzyme could hold the key to longer life and healthier aging. This is what researchers around Eyleen Jorgelina O’Rourke from the University of Virginia (UVA) report in the journal “Current Biology”. In laboratory worms of the species Caenorhabditis elegans (C. elegans), they ensured that the animals produced more of the so-called alcohol dehydrogenase-1 (ADH-1). Not only did the worms live 50 percent longer, they also stayed healthy longer.
ADH-1 breaks down various alcohols in the body. It not only breaks down the ethanol from beer and wine, but also the toxic glycerol that is produced when fat is broken down. “Glycerol is toxic to cells because it leads to the oxidation of proteins and other cell components. Ultimately, it leads to dysfunction of cells and organ dysfunction,” says O’Rourke.
In old age: body fat becomes fatal
Fats are each made up of three fatty acids held together by a backbone of glycerol. So far, doctors have only paid attention to the fatty acids during the annual health check. In the future, they should probably also keep an eye on glycerol. O’Rourke says that as we age, it can accumulate in excess and cause problems for two reasons. On the one hand, the body then often produces less ADH-1 and can therefore no longer keep up with the breakdown of glycerol. On the other hand, we often accumulate more body fat as we get older.
Since these fat deposits are regularly renewed, i.e. older fatty tissue is broken down and new one is stored, a lot of glycerol is constantly produced. Then normal ADH-1 production can no longer keep up. In both cases, and when they occur at the same time, the remaining glycerol causes damage.
To test whether more ADH-1 helps avoid these problems, O’Rourke’s team upregulated the activity of the associated gene in C. elegans. “We found that by increasing enzyme activity and eliminating these toxic by-products of fat breakdown, we can not only extend the lifespan of laboratory animals, but also the length of time they are healthy throughout their lifespan,” explains O’ Rourke.
Gene in, gene out
In order to provide even more evidence of the causal connection between ADH-1 activity and health and lifespan, the researchers also investigated what happens when the gene is switched off. In fact, the animals not only died earlier, but also contracted age-related diseases earlier.
In the next step, O’Rourke’s team also examined the activity of the ADH-1 gene in mammals such as rats, rhesus monkeys and humans. They found that activity is particularly high when they are on a calorie-reduced diet while still getting all the essential vitamins. “This condition has been shown for decades to increase health and lifespan. We found that this enzyme is hyperactive under these conditions,” says O’Rourke. “So we don’t prove that this enzyme extends lifespan. But under the conditions under which lifespan is extended, the enzyme is active,” says the researcher.
So far, there has only been a correlation in more highly developed animals, but no causality has yet been proven. “Of course we can’t genetically manipulate humans (like worms, editor’s note),” says O’Rourke. As a next step, she therefore plans to test in mice whether hyperactivation of the ADH-1 enzyme increases the animals’ health and lifespan. At the same time, she also wants to test in human cell cultures whether upregulation of the enzyme can reduce signs of aging at the cellular level. If this is the case, she wants to look for substances that can upregulate the enzyme particularly well.
Further research
When asked what disadvantages such an influence could have, the researcher replies: “The only disadvantage we have found so far is that the number of offspring is lower than in unaltered animals.” That needs to be further investigated. It should also be noted that in addition to breaking down glycerol, the ADH-1 enzyme can also directly trigger fat loss. When activated, the animals are thinner.
“This might be good for adults, but not necessarily for developing animals or children, so in all experiments so far we’ve activated the process after the animals have reached adulthood,” reports O’Rourke. They still have to figure out when is a good time to start and what dose is right.
Because the enzyme is also most active in the liver, the researcher wants to find out whether it is enough to activate the enzyme there. If not, it’s important to find out if body-wide activation would cause problems.
But all of that is still further in the future. The team is initially looking for private investors and industrial investors from the pharmaceutical industry in order to be able to finance the next stages of research.
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