Is the use of senolytics exaggerated?
Scientists from the Institute of Cytology of the Russian Academy of Sciences have refuted the generally accepted principle of action of drugs against cellular aging
Press Service of the Russian Science Foundation
Scientists from the Institute of Cytology of the Russian Academy of Sciences have demonstrated that not all aging cells acquire resistance to programmed "suicide", which means that senolytic drugs designed to fight them are not universal and do not work at all as previously thought. Experts believed that these substances suppress the mechanisms that ensure the resistance of old cells to death, but the results of the new work refute this scenario
Joint cultivation of young and old stem cells
Cells age either in response to stressful effects that damage DNA, or due to the exhaustion of the allotted limit of divisions. Aging cells completely stop dividing, but they do not die, but remain in the tissues. At the same time, the work of most of their systems is disrupted, because they are not able to perform their usual functions.
At the same time, aging cells secrete many substances into the extracellular space that can cause malignant degeneration of precancerous cells. They also provoke inflammatory reactions that worsen health, as well as increase the risk of developing serious diseases, such as Alzheimer's and Parkinson's diseases, osteoporosis, osteoarthritis, heart failure and many others.
Usually aging cells destroy the immune system, but with age or with various disorders, it ceases to cope. In this case, it is necessary to use special preparations of senolytics — medicinal compounds that selectively affect aging cells. As it was believed until recently, the principle of their action is based on fighting the resistance of old cells to apoptosis — programmed "suicide". However, as the authors of the work have shown, this may not be the case at all.
"We conducted a number of experiments on aging cells of various natures, including cancer and stem cells, and found out that not all of them develop resistance to apoptosis. Moreover, it turned out that senolytics act only on those who have not acquired this stability during aging. This means that the mechanism of their action differs from the generally accepted one. Probably, they do not affect anti—apoptotic pathways, but other mechanisms important for cell survival, but those that are changed and vulnerable in old cells, not young ones," explains senior researcher, head of the group of mechanisms of cellular aging of the INC RAS Alexandra Borodkina.
Scientists from The Institute of Cytology of the Russian Academy of Sciences conducted experiments on human mesenchymal stem cells (MSCs), which are capable of transforming into different types of cells: fat, bone, cartilage, muscle and nerve. Their aging has many undesirable consequences, up to the disruption of tissue regeneration in the body. To simulate aging, scientists exposed stem cells to DNA-damaging compounds and hydrogen peroxide, which triggers oxidative stress, and also simply grew a culture for a long time. Then the authors tried to kill the cells with the help of senolytics.
"All types of aging MSCs turned out to be immune to the action of drugs precisely because of resistance to apoptosis. If they additionally suppress the activity of proteins that determine this property, they can be made sensitive to senolysis," notes Alexandra Borodkina.
Scientists have come to the conclusion that the senolytics developed to date are not effective against old mesenchymal stem cells. In order to trigger their death with the help of known drugs, an additional impact on the protection against programmed death is necessary. An alternative option may be the search and development of more universal senolytics — which is what the researchers of the INC RAS are doing now.
The work carried out with the support of a grant from the Presidential Program of the Russian Science Foundation (RNF) can be found on the pages of the journal Cellular and Molecular Life Sciences (Deryabin et al., Apoptosis resistance of senescent cells is an intrinsic barrier for senolysis induced by cardiac glycosides).
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