Cellular aging can be slowed down by oxidants

At high concentrations, reactive oxygen species, known as oxidants, are harmful to the cells of all organisms and have been linked to aging. But a study from Chalmers University of Technology, Sweden, has now shown that low levels of oxidizing hydrogen peroxide can stimulate an enzyme that helps slow the aging of yeast cells.

An advantage of antioxidants, such as vitamins C and E, is that they neutralize reactive oxygen species, known as oxidants, which could otherwise react with important molecules in the body and destroy their biological functions. For example, larger amounts of oxidants can cause severe damage to DNA, cell membranes and proteins. Our cells have therefore developed powerful defense mechanisms to get rid of these oxidants, which form in our normal metabolism.

Previously it was believed that oxidants are only harmful, but recently scientists have begun to understand that they also have positive functions. Now, new research from Chalmers University of Technology shows that the well-known oxidizing hydrogen peroxide can actually slow the aging of yeast cells. Hydrogen peroxide is a chemical used, among other things, for whitening hair and teeth. It is also one of the metabolically produced oxidants that is harmful at higher concentrations.

Chalmers researchers studied the Tsa1 enzyme, which is part of a group of antioxidants called peroxiredoxins.

“Previous studies on these enzymes have shown that they participate in yeast cell defenses against harmful oxidants,” says Mikael Molin, who leads the research team at Chalmers Department of Biology and Biological Engineering. “But peroxyroxins also help extend the lifespan of cells when they are subject to calorie restriction. The mechanisms underlying these functions are not yet fully understood.”

Researchers know that a reduced calorie intake can significantly extend the lifespan of a variety of organisms, from yeast to monkeys. Several research groups, including that of Mikael Molin, have also shown that stimulating peroxiredoxin activity in particular is what slows down cell aging in organisms such as yeasts, flies and worms, when they receive fewer calories than normal through the food.

“Now, we have found a new function of Tsa1,” says Cecilia Picazo, a postdoctoral researcher at Chalmers Division of Systems and Synthetic Biology. “Previously, we thought that this enzyme simply neutralized reactive oxygen species. But now, we have shown that Tsa1 actually requires the activation of a certain amount of hydrogen peroxide to participate in the slowing process of aging of yeast cells. “.

Surprisingly, the study shows that Tsa1 does not affect hydrogen peroxide levels in aged yeast cells. Conversely, Tsa1 uses small amounts of hydrogen peroxide to reduce the activity of a central signaling pathway when cells receive fewer calories. The effects of this ultimately lead to a slowdown in cell division and the processes associated with the formation of the cell’s building blocks. The cell’s defenses against stress are also stimulated, which makes them age more slowly.

“Signal pathways that are affected by calorie intake can play a central role in aging by detecting the state of many cellular processes and controlling them,” says Mikael Molin. “By studying this, we hope to understand the molecular causes behind why the onset of many common diseases such as cancer, Alzheimer’s and diabetes show a steep increase with age.”

The fact that researchers have now taken a step closer to understanding the mechanisms behind how oxidants can actually slow the aging process could lead to new studies, for example looking for peroxiredoxin-stimulating drugs, or testing whether diseases age-related can be slowed down by other drugs that increase the positive effects of oxidants in the body.

Chalmers researchers showed a mechanism for how the peroxiredoxin enzyme Tsa1 directly controls a central signaling pathway. It slows down aging by oxidizing an amino acid into another enzyme, protein kinase A, which is important for metabolic regulation. Oxidation reduces the activity of protein kinase A by destabilizing a portion of the enzyme that binds to other molecules. Thus, nutrient signaling via protein kinase A is reduced, which in turn reduces cell division and stimulates their defense against stress.

Other studies have also shown that low levels of reactive oxygen species can be linked to several positive health effects. These oxidants form in the mitochondria, the cell’s powerhouse, and the mitormesis process can be observed in many organisms from yeast to mice. In mice, tumor growth was slowed by mitormesis, while in roundworms it was possible to link both peroxiredoxins and mitormesis to the ability of the type 2 diabetes drug metformin to slow cellular aging.

Metformin is also relevant in the search for drugs that can reduce the risk of older people being severely affected by COVID-19. Studies in China and the United States have produced promising results, and one theory is that metformin may counteract the deterioration of the immune system caused by aging.