A study conducted by U.S. scientists shows new ways to treat congenital dyskeratosis and other diseases associated with telomere defects and premature aging of cells. An article about this work was published in the journal Stem Cell.

Telomeres are the end sites of chromosomes that serve protective and regulatory functions. In each cycle of cell division telomere sequences shorten due to the peculiarities of the DNA polymerase enzyme. This fact became the basis for the so-called marginotomy, a theory that views telomeres as similar to a chromosomal timer that counts down the cell divisions remaining until cell death.

Some cells in the body (e.g., stem cells) synthesize the telomerase enzyme, which completes the chromosomes after divisions and allows cells to remain “forever young. If telomerase expression is disrupted, body tissues begin to age prematurely. This can lead to the development of a whole range of diseases – in addition to the aforementioned dyskeratosis, pulmonary fibrosis and non-alcoholic cirrhosis of the liver.

Dyskeratosis itself can be caused by one of many mutations. Most of these mutations disrupt telomerase formation or function, particularly by destroying two molecules called TERT and TERC, the main subunits of the enzyme. TERT is a telomeric reverse transcriptase, a molecule capable of catalyzing DNA synthesis on the RNA matrix. TERC is the very matrix required for telomere completion.

Microphotograph of chromosomes with labeled telomeres / © Stat
Microphotograph of chromosomes with tagged telomeres / © Stat
The authors of a new paper led by Sunit Agarwal showed several years ago that the PARN gene is involved in the development of telomere diseases. Its proper functioning is important for normal TERC formation and stabilization. In the current study, scientists focused on PAPD5, a protein that suppresses PARN and destabilizes the TERC molecule.

The scientists conducted extensive screening studies to identify PAPD5 inhibitors, testing more than 100,000 known chemicals. Having obtained an initial list of 480 candidates, the scientists further narrowed their choice down to a small number of potential inhibitors. These molecules were tested on cell cultures obtained from patients with dyskeratosis.

All of the tested substances increased TERC levels in the cells and promoted telomere regeneration to their normal length. However, the more difficult task was to find out whether the treatment would be safe and specific, affecting only stem cells containing the desired molecules.

To do this, the selected compounds were tested on laboratory mice, which had previously been transplanted human stem cells with mutations in the PARN gene, leading to the development of dyskeratosis. The action of PAPD5 inhibitors led to restoration of telomere length in the transplanted cells without affecting the animals’ ability to form different types of blood cells.

In the future, Agarwal and his colleagues hope to confirm the benefits of inhibiting PAPD5 for other diseases associated with telomere and telomerase malfunction – and possibly affect the aging process in general. The two substances, codenamed BCH001 and RG7834, are considered the most promising of all potential drug candidates by the scientists.

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Telomeres are the end sections of chromosomes. The telomeric portions of chromosomes are characterized by their lack of ability to attach to other chromosomes or their fragments and serve a protective function. The genes in question are TERT and TERC, which are present in 51% and 72% of the world’s population, respectively, but their variations are very rare.

There is a high barrier to the development of gliomas, and perhaps because the brain has special protection.

The TERT and TERC genes are responsible for lengthening telomeres. However, as Wrench notes, this has both positive and negative qualities. Long telomeres are not only responsible for longevity, but also lead to the development of glioma.

Glioma is a tumor that is part of a heterogeneous group and is of neuroectodermal origin. It is the most common primary brain tumor.

Although longer telomeres may be a good thing for humans, reducing some health risks and slowing down aging, they can also cause some cells to live longer than they should, and this, it is suggested, may be a sign of cancer development.

In the study, scientists analyzed the genomic base of nearly 40,000 people. They found that short telomeres were associated with cardiovascular disease.

Wrench and her colleagues examined data from 1,644 glioma patients and 7,736 healthy individuals. She found that most glioma patients had variations in TERT and TERC genes as well as enlarged telomeres.

Scientists are to continue the study and study the influence of the TERT gene in the development of lung, prostate, breast, leukemia and colorectal cancers.

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The scientists chose a simple way to check. They used statistics from the National Health and Nutrition Examination Survey, a program run by the U.S. Department of Health and Human Services. A total of 1,954 questionnaires were used in the study of women who were screened between 1999 and 2002, because that was the time period when physicians measured patients’ telomere length.

The comparison showed that women who gave birth had shorter telomeres compared to the control group, a difference estimated by scientists at 11 years. This figure is even higher than in studies related to smoking and obesity. Dr. Anne Pollack, who led the work, commented on the observation:

“So far, we can’t say unequivocally that shortened telomeres are related to childbirth. Perhaps they were shorter initially, or perhaps stress or other factors contributed to the decrease in length. More research will be needed to determine the causes.”

The authors of the paper also note that they did not obtain data on women’s reproductive status, stress levels or other factors during the study. Telomere size is not always associated with positive trends, with some scientists suggesting that long telomeres contribute to cancer.

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