Telomerase Repair Tablet
Stem cell aging drug successfully tested on mice
Alice Bakhareva, N+1
Small molecules restored the work of telomerase and lengthened telomeres in the stem cell culture of patients with hereditary telomeric disease. The substances were added to the water of mice that had been transplanted stem cells with similar mutations. As a result, telomerases began to work normally in these cells, and telomeres lengthened.
DNA polymerases (enzymes that replicate DNA) they do not know how to copy the ends of molecules, and with each cell division the chromosomes become a little shorter. In order not to lose important information at the same time, telomeres are located at the ends of chromosomes – non-coding sections of DNA. They also have a protective function – telomeres do not allow different chromosomes to stick together.
The length of telomeres is associated with cellular aging: when they become too short, the cell triggers the mechanism of aging and death in order to avoid the gluing of chromosomes and damage to genetic material. Stem cells divide a lot (after all, this is their main function), and they have the enzyme telomerase, which lengthens telomeres and allows cells to be immortal.
Mutations that disrupt the work of telomerases cause a number of hereditary diseases. One of the mechanisms of such diseases is mutations in the ribonuclease gene, which regulates the formation of telomerase RNA, the template by which the enzyme completes telomeres. If you turn off the corrupted ribonuclease gene (PAPD5), normal telomerase RNAs are formed and telomeres are lengthened.
Scientists from the USA led by Suneet Agarwal from Boston Children's Hospital found a small molecule BCH001, which specifically inhibited mutant ribonuclease. The effect of the substance was tested on the stem cell culture of patients with congenital dyskeratosis, hereditary telomere disease.
When the substance BCH001 is added to the culture of mutant stem cells, their telomeres are lengthened. Figures from the article Nagpal et al. Small-Molecule PAPD5 Inhibitors Restore Telomerase Activity in Patient Stem Cells, published in the journal Cell Stem Cell.
In addition, the researchers tested the effect of dihydroquinolysinones on PAPD5 – substances that block hepatitis B viruses. A recent study found that the same ribonuclease is involved in the pathogenesis of hepatitis B, and the authors of the work suggested that dihydroquinolysinones may act on it.
The structure of the molecules BCH001 (top) and dihydroquinolysinone RG7834 (bottom).
The substances were then tested in vivo. To do this, the ribonuclease gene was disrupted in human bone marrow stem cells using CRISPR/Cas9. These cells were transplanted into mice, and then dihydroquinolysinone was added to their drinking water.
In the stem cell culture to which BCH001 was added, normal telomerase RNA was formed, and telomeres were lengthened. At the same time, other cellular enzymes worked normally. Dihydroquinolysinones also restored the production of telomerase RNA in stem cell culture.
In mice that were transplanted human bone marrow stem cells with damaged ribonuclease, as a result of oral administration of dihydroquinolysinone in the transplanted tissues, the amount of telomerase RNA increased and telomeres lengthened. The drug did not cause side effects even after months of taking it.
In 2018, scientists found out the detailed structure of telomerase. It was possible to understand the structure of the enzyme using cryo-electron microscopy.
Portal "Eternal youth" http://vechnayamolodost.ru