Telomerase activation: new data on the "youth enzyme"

New features of the "youth enzyme"
Anna Sablina, Eternalmind.ruRecently, two studies have been conducted that support the ability of increasing telomerase expression to improve the functioning of human immune cells and prolong the youth of mice.

In the second study, the increased risk of malignant neoplasms from increased telomerase activity was compensated by genes of a cancer-resistant mouse line.

Many hopes were associated with the enzyme telomerase as a source of "eternal youth", because it is this enzyme that directly affects aging at the cellular level. Since each DNA strand is synthesized according to the template of the mother strand, and DNA polymerase needs a primer to work - a small section of RNA to the end of which it attaches new nucleotides — when DNA is doubled, the chromosome is not completely reduplicated, and its length decreases over time. In healthy cells, there is DNA at the ends of chromosomes with repeating sequences that carry a structural function. But as cell divisions progress, these areas (telomeres), decreasing, come to naught, and the DNA of genes encoding proteins begins to under-replicate. Such cells become non—viable, which is due to the presence of the so-called Hayflick limit - a somatic cell (which is not a stem, germ pathway or cancer cell) cannot share more than 60-80 times, when approaching this limit, the activity of reproduction decreases, the mechanism of programmed cell death is triggered in the cells. The enzyme telomerase, active in cancer, stem cells and germ pathway cells, can superstructure telomeric DNA sections using a small RNA available in its composition as a matrix. Cells in which telomerase is active can divide an unlimited number of times. However, in differentiating cells that begin to perform some specific function in the body, losing the potency of differentiation into other cell types, the level of telomerase expression usually drops sharply.

As part of the fight against HIV, immunologist Rita Effros from the University of California (Los Angeles) performed genetic manipulations with immune T-killer cells, as a result of which telomerase activity sharply increased in them. T-killers are responsible for fighting viral infections in the body by killing virus-infected cells, since it is impossible to remove the virus that has entered the cell. Immune cells, unlike other differentiated cells, increase telomerase activity when activated. However, with aging and chronic HIV-1 infection, the proportion of non-functional T cells with reduced telomerase activity increases dramatically. The genetic increase in telomerase activity led to a sharp increase in the ability of T-killers to fight viral infections, but such gene therapy was considered too dangerous for medical practice.

In later experiments, Effros moved on to research on the low-molecular-weight substance TAT2 (telomerase activator), developed by the Geron organization in Menlo Park, California. It dramatically enhances the synthesis of telomerase without changing DNA, and also slows down the shortening of telomeres, enhances the ability of cells to divide and enhances the production of cytokines and chemokines, which is very important for the coordinated functioning of the immune system. When the T-killers of HIV-infected people were exposed to TAT2, their ability to fight the virus increased, which suggests that TAT2 can be used as an addition to existing drugs to fight retroviruses. This is the first direct pharmacological effect on telomerase to improve immune function (The Journal of Immunology, vol 181, p 7400).

The idea of the special importance of telomerase for immunological processes is supported by an earlier study, which showed that in some HIV-infected people who have not shown symptoms of AIDS for years, T-killers have high telomerase activity and, accordingly, longer telomeres. Since T cells fight many viruses, TAT2 can eventually be used to increase resistance to a variety of diseases.

There remains some concern about the safety of pharmacological effects on telomerase, not least because cancer cells have higher activity than normal ones. Arne Akbar, an immunologist at University College London, says that with any exposure that enhances telomerase activity, you can get unwanted active cell reproduction, as in cancer.

However, when exposed to TAT2 on cancer cells, their telomerase activity did not change. Under its action, the dynamics of the population of immune cells cultured with the virus, which may be the cause of malignant transformation, also did not change.

Previously, experiments were conducted to increase the activity of telomerase in mice, but this only shortened their life expectancy, because increased telomerase activity contributes to the appearance of tumors.

Maria Blasco of the Spanish National Cancer Centre, Madrid, and her colleagues crossed mice of a line genetically modified to be resistant to cancer with mice that, as a result of genetic modification, produce telomerase 10 times the normal level in epithelial tissue (which lines the surfaces and cavities of the body). These animals lived up to 50% longer than normal mice (Cell, dx.doi.org/10.1016/j.cell.2008.09.034 ).

The Blasco mice also had less subcutaneous fat, healthier epithelial tissue, good neuromuscular coordination and glucose tolerance, which are generally signs of youth. Increased telomerase activity also seemed to have a beneficial effect on the brain and muscles of animals, although it was not expressed in these tissues.

Effros cautions against concluding that this means we can prevent aging in humans. She believes that it is very difficult to extrapolate data from mouse aging to human aging. In particular, she notes that mice have longer telomeres than humans, and laboratory mice are grown, unlike humans, in "sterile" conditions.

Blasco, however, is optimistic that a similar approach can help prolong human lives over time. She suggests that treatment can also be combined with anti-cancer drugs to compensate for the increased risk of malignant transformation.

Portal "Eternal youth" www.vechnayamolodost.ru
03.12.2008