Male hormone reverses cell aging in clinical trial

Study by Brazilian and US researchers published in The New England Journal of Medicine evidences the possibility of inducing synthesis of telomerase, the "cellular elixir of youth".

By Karina Toledo  |  Agência FAPESP – Telomerase, an enzyme naturally found in the human organism, is the closest of all known substances to a “cellular elixir of youth.” In a recent study published in The New England Journal of Medicine, Brazilian and US researchers show that sex hormones can stimulate production of this enzyme.

The strategy was tested in patients with genetic diseases associated with mutations in the gene that codes for telomerase, such as aplastic anemia and pulmonary fibrosis. The authors say that the results suggest that the approach can combat the damage caused to the organism by telomerase deficiency.

The study was performed by Brazilian researchers in collaboration with colleagues at the National Institutes of Health (NIH) in the US. Among the Brazilian scientists involved were Phillip Scheinberg, Head of Clinical Hematology at Hospital São José (a unit of Beneficência Portuguesa de São Paulo), and Rodrigo Calado, a professor at the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP) and a member of the Center for Cell-Based Therapy (CTC), one of the Research, Innovation and Dissemination Centers (RIDCs) supported by FAPESP.

“One of the processes associated with aging is progressive shortening of telomeres, DNA-protecting structures at the ends of chromosomes, like the plastic tips on shoelaces,” Calado said. “Each time a cell divides, its telomeres get shorter. Eventually, the cell can’t replicate anymore and dies or becomes senescent. However, telomerase can keep the length of telomeres intact, even after cell division.”

In practice, he added, telomere length is a laboratory measure of a cell’s “age.” Some cells avoid aging by using telomerase to lengthen their telomeres through the addition of DNA sequences, thereby maintaining their capacity to multiply and “stay young.”

In an embryo, where tissue is still in the formative stage, telomerase is expressed by practically every cell. After this period, only cells that are constantly dividing, such as hematopoietic (blood-forming) stem cells, which can differentiate into a variety of specialized cells, continue to produce telomerase.

“Aplastic anemia is one of the diseases that can be caused by telomerase deficiency,” Calado said. “Bone marrow stem cells age prematurely and fail to produce enough red blood cells, white blood cells and platelets, making the patient dependent on blood transfusions and more susceptible to infections.”

A dearth of telomerase can also affect several organs including the liver and lungs, potentially leading to cirrhosis and pulmonary fibrosis, and is believed to increase the risk of some cancers by 1,200-fold.

According to Calado, clinical evidence that patients with aplastic anemia respond well to treatment with male hormones (androgens) has accumulated since the 1960s.

In 2009, Calado and collaborators published an article in the journal Blood showing that androgens, which are converted into estrogens in humans, bind to female hormone receptors in the telomerase gene promoter region and thereby stimulate expression of the enzyme in cells.

“The study we’ve just published was designed to find out whether the effect we’d observed in the lab also occurred in humans, and the results indicate that it does,” Calado said.

Instead of estrogen, the researchers treated the patients with androgen, he explained, because it has long been used as a drug in cases of congenital anemia and offers the advantage of stimulating an increase in the mass of hemoglobin (red blood cells), which estrogen cannot do.

Clinical trial

Treatment with the steroid danazol, a synthetic male hormone, was tested for two years in 27 patients with aplastic anemia owing to telomerase gene mutations. Some also suffered from pulmonary fibrosis, a disease characterized by progressive scarring of the lungs and a gradual decline in lung function.

“In a healthy adult, telomere length varies from 7,000 to 9,000 base pairs on average. A normal person’s telomeres lose 50 to 60 base pairs per year, but a patient with telomerase deficiency can lose between 100 and 300 base pairs per year,” Calado said. “In the patients who received danazol, telomere length increased by 386 base pairs on average over two years.”

In addition, hemoglobin mass rose from 9 grams per deciliter (g/dL) to 11 g/dL on average. A person without anemia normally has between 12 and 16 g/dL, but the improvement observed in these subjects was sufficient to rid them of transfusion dependency.

In the patients with pulmonary fibrosis, degeneration was halted. This can be considered significant progress in the case of a disease for which there is no treatment.

“On completion of the protocol, the medication was interrupted, and we observed a fall in all counts. Several patients resumed the medication with smaller doses, individually adjusted to minimize side effects,” Calado said.

Like other anabolic steroids, danazol can be toxic for the liver and cause testicular atrophy in men and a degree of masculinization in women. Some patients eventually dropped out of the trial with complaints of muscle cramps and swelling.

In a new protocol currently in progress at the University of São Paulo’s Ribeirao Preto Blood Center, the same kind of approach is being tested with nandrolone, an injectable male hormone. The study is supported by FAPESP and the National Council for Scientific & Technological Development (CNPq).

“The effects of nandrolone on the liver are far less severe than those of danazol, and the preliminary results are showing an improvement, at least from the hematological standpoint. Telomeres have yet to be evaluated,” Calado said.

Another future possibility, he added, is to study the development of drugs capable of binding to the estrogen receptor and stimulating telomerase production without the side effects of anabolic hormones.

Longevity

Although the results of the study suggest that drugs can be used to reverse one of the biological drivers of aging, it is not yet clear whether the benefits of treatment would surpass the risks in healthy people, especially if the treatment involved the use of sex hormones.

“This would have to be studied on the basis of a research protocol,” Calado said. “For example, post-menopausal hormone replacement therapy offers a number of benefits, including maintenance of bone mass, libido and cardiovascular health. However, it increases the risk of breast cancer, so it’s no longer recommended indiscriminately.”

Some groups, such as patients undergoing chemotherapy or radiotherapy, may benefit from drugs that stimulate telomerase in the future. “Cancer treatments tend to accelerate cellular aging, and this could perhaps be reversed by stimulating telomerase,” he added. “However, excessive telomere lengthening might facilitate the development of cancer by favoring cell proliferation. All this needs to be investigated further.”

The article “Danazol Treatment for Telomere Diseases” (doi: 10.1056/NEJMoa1515319) can be read at nejm.org/doi/pdf/10.1056/NEJMoa1515319.