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In the embryonic stage, when all tissues are forming, telomerase is expressed in virtually all cells

Image: Wikimedia Commons

The enzyme telomerase – naturally found in the human body – is the known substance that comes closest to the concept of the cellular “elixir of youth”.

In a recent study, published in the New England Journal of Medicine, Brazilian and US researchers showed that it is possible to stimulate the production of this protein with the use of sex hormones.

The strategy was tested in patients with genetic diseases associated with mutations in the gene encoding telomerase, such as aplastic anemia and pulmonary fibrosis, and was shown to be able to combat the damage to the body caused by the enzyme deficiency.

The study was carried out in collaboration with the National Institutes of Health (NIH) of the United States. Among the Brazilian authors are Phillip Scheinberg, head of the Hematology Service at Hospital São José, Associação Beneficência Portuguesa de São Paulo, and Rodrigo Calado, professor at the Faculty of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP) and member of the Cell Therapy Center ( CTC ), one of the CEPIDs supported by the Foundation for Research Support of the State of São Paulo (Fapesp).

“One of the processes associated with aging is the shortening of telomeres, structures existing at the ends of chromosomes that serve to protect the DNA, as well as the plastic at the ends of shoelaces. Every time the cell divides, the telomeres shrink in size, until a time when the cell can no longer proliferate and die or go into senescence. But the telomerase enzyme is able to keep telomere length intact even after cell division,” explained Calado.

In practice, the researcher said, the size of telomeres makes it possible to measure the “age” of a cell, which can be measured in the laboratory. In order to prevent this aging, some cells are able, through telomerase, to lengthen the telomeres by adding DNA sequences, thus maintaining their ability to multiply and their “youth”.

In the embryonic stage, when all tissues are forming, telomerase is expressed in virtually all cells. After this period, only those in constant division continue to synthesize the enzyme, as is the case of hematopoietic stem cells, which give rise to various components of the blood.

“Aplastic anemia is one of the diseases that can be caused by telomerase deficiency. Premature aging of bone marrow stem cells occurs and, consequently, insufficient production of white and red blood cells and platelets. The carrier is dependent on periodic blood transfusions and is more susceptible to infections”, explained Calado.

A lack of telomerase can also affect the functioning of the liver (cirrhosis), lungs (fibrosis), and other organs, in addition to increasing the risk of some cancers up to 1200-fold.

Since the 1960s, said the CTC researcher, there has been clinical evidence that patients with aplastic anemia respond well to treatment with male hormones (androgens).

In 2009, Calado and collaborators showed in an article published in the journal Blood that androgens – which in the human body are transformed into estrogens – bind to female hormone receptors in the promoter region of the telomerase gene and, thus, stimulate the enzyme's synthesis in the cells.

“This study that we have just published aimed to see if this effect that we had observed in the laboratory also occurred in humans, and the results indicate that it was”, said Calado.

According to the researcher, instead of estrogen, we chose to treat patients with androgen because this type of drug has been used for a long time in cases of congenital anemia and offers the advantage of stimulating an increase in hemoglobin mass (red blood cells) – something the female hormone is not capable of.

clinical trial

Treatment with the steroid danazol – a synthetic male hormone – was tested for two years in 27 patients with a mutation in the telomerase gene and who suffered from aplastic anemia. Some also suffered from pulmonary fibrosis, a disease characterized by the replacement of functional lung tissue by scar tissue.

“The telomere of a healthy adult has an average of 7,000 to 9,000 base pairs. A normal individual loses on average, per year, between 50 and 60 base pairs; a patient with telomerase deficiency can lose 100 to 300 base pairs per year. However, after two years, patients who received danazol presented an average length of 386 base pairs in the telomeres,” said Calado.

In addition, the hemoglobin mass increased from 9 grams per deciliter to 11 g/dL, on average. A person without anemia usually has between 12g/dL and 16g/dL, but the improvement observed was enough to make the patients independent of blood transfusion.

In patients with pulmonary fibrosis, the degenerative picture has stopped evolving – which is a great advance because it is a disease for which there is no treatment.

“After the end of the protocol, the medication was stopped and we noticed a drop in the counts. Several patients went back to taking the medication, but now in smaller doses, individually adjusted to minimize side effects,” said Calado.

Like other anabolic steroids, danazol can be toxic to the liver, cause testicular atrophy in the case of men, and some masculinization in the case of women. Some patients who were initially part of the study dropped out during the process due to discomfort such as cramps and swelling.

In a new protocol currently underway at USP's Blood Center in Ribeirão Preto, the same type of approach is being tested with another injectable male hormone called nandrolone. The study is supported by FAPESP and by the National Council for Scientific and Technological Development (CNPq).

“The effects of nandrolone on the liver are much smaller than those of danazol and preliminary results are showing improvement, at least from a hematological point of view. The telomeres are yet to be evaluated,” said Calado.

Another future possibility, pondered the researcher, is to study the development of drugs capable of binding to the estrogen receptor and stimulating the telomerase enzyme without causing the other effects of anabolic hormones in the body.

Longevity

Although the results of the study indicate that it is possible to reverse one of the biological factors of aging with drug use, it is still unclear whether, in healthy people, the benefits of treatment would outweigh the risks, especially if the use of sex hormones is involved.

“This would need to be studied within a research protocol. For example, in the case of post-menopausal hormone replacement, there are a number of benefits: maintenance of bone mass, libido, cardiovascular health. On the other hand, there is an increased risk of breast cancer. Today, this treatment is no longer recommended indiscriminately”, commented Calado.

In the researcher's assessment, it is possible that some groups of people – such as patients undergoing chemotherapy and radiotherapy – may benefit in the future from drugs capable of stimulating telomerase.

“Cancer treatments tend to accelerate cell aging and perhaps this can be reversed with telomerase stimulation. On the other hand, excessively stretching the telomeres can facilitate the development of cancer, as it favors cell proliferation. All of this will still have to be investigated”, he stated.

The article Danazol Treatment for Telomere Diseases (doi: 10.1056/NEJMoa1515319) can be read here.

Source: FAPESP Agency