A useful stressor
A "slight disorder" in DNA prolonged the life of yeast no worse than starvation
This is another form of stress, which in small doses can be useful for cells
Polina Loseva, "The Attic"
During the life of a cell, it can face many stressful factors: poisoning with toxins, lack of food, hypoxia. But, nevertheless, all of them can prolong its existence if they act in small quantities. Researchers from Houston have found another type of stress that affects cells – DNA unwinding. It triggers the same signaling pathways as fasting – a method now recognized as one of the most promising in life extension.
One of the signs of an aging cell is the repackaging of DNA in the nucleus. At the same time, some of its sections unfold, making the information located on them more accessible, but most of it, on the contrary, is tightly wound on histone proteins. If DNA suddenly begins to actively unwind, then this becomes an alarming signal for the cell: it can either be a consequence of dangerous mutations, or become their cause. At this point, the cell should stop multiplying, start the DNA repair mechanisms and restore its original structure. These and other processes are included in the reaction of cells to stress.
In addition to DNA unwinding, other factors can cause stress: free radicals formed as a result of respiration, toxins (for example, ethyl alcohol), ionizing radiation, temperature changes, and so on. All of them in large quantities lead to cell aging and death of the body. However, it has long been known that in small doses, all this, on the contrary, stimulates the growth and division of cells, since it triggers internal repair mechanisms in them and thus increases their viability. This effect is called hormesis, and the factors causing it are called gormetins.
It is often difficult to draw a line between small, useful, and large, destructive doses of gormetins (as in the case of alcohol, for example). However, there is a lot of data on how stress prolongs life – at least in model organisms. The standard of gormetin, with which other factors are compared and according to which the clock of biological age is calibrated, is now considered to be calorie restriction in daily food, that is, fasting.
Scientists from Houston suggested that DNA unwinding can also become a hormone for cells, and tested their hypothesis on yeast. They have two copies of the genes encoding the main histones. The auxiliary copy supplies about 15% of all histones of the cell, and the main copy supplies the remaining 85%. If you turn off both, yeast quickly dies, because in the absence of "coils for winding" DNA loses its spatial structure.
Therefore, the researchers first separately disabled the main copy and found that this significantly shortens the life of cells. Ordinary yeast aged (stopped dividing) after about 37 rounds of reproduction, and mutant yeast aged after 30. But cells deprived of an auxiliary copy unexpectedly turned out to be more tenacious and withstood all 40 divisions. Thus, a small unwinding of DNA turned out to be a useful stress for the cell.
To test exactly how the absence of histones triggers stress in the cell, scientists took turns introducing additional mutations into the yeast genome. If a new mutation, in comparison with the absence of an auxiliary copy, additionally prolongs life, it means that it affects a new mechanism of stress. If there is no additional effect from the mutation, then both the gene in which it is located and the histones are responsible for the same signaling pathway.
After checking several genes, the researchers found that histones act through the protein TOR, which is already known as a regulator of aging in different organisms. When TOR is active, it triggers cell growth and division, while the mechanisms of intracellular repair lose priority, which soon leads to the fact that it wears out and ages. When TOR does not work, growth and division are suspended, but the cell gets the opportunity to restore the integrity of its molecules and organelles. Apparently, a "slight disorder" in the DNA stacking blocks the work of TOR, thereby prolonging the life of the cell. It is significant that turning off the auxiliary copy of histones affected the life of yeast in the same way as the mutation simulating calorie restriction.
The researchers suggested that this mechanism – the occurrence of mild stress in response to a lack of histones – may exist not only in yeast, but also in multicellular animals. They used the articles of their predecessors, who studied the expression of genes in nematode, drosophila and mouse cells carrying a mutation in histone genes. It turned out that most of the genes whose functions are mainly related to the TOR signaling pathway stop working under "histone stress" in both yeast and multicellular. This means that in the list of gormetins – candidates for ways to prolong life – another one has appeared, comparable in strength and mechanisms of action with calorie restriction.
Article by Yu et al. Cellular response to moderate chromatin architectural defects promotes longevity is published in the journal Science Advances.
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