The impact of the telomerase enzyme’s discovery cannot be overstated, as its importance to cell biology was recognized in 2009 with the awarding of the Nobel Prize in Physiology or Medicine. Over the years, researchers have come understand more closely the molecular mechanisms this protein utilizes during the cell cycle and maturation, leading it too often to be referred to as the “fountain of youth” molecule. Now, a recent study by investigators in the U.S. and Brazil has shown that male sex hormones can stimulate production of the telomerase enzyme—providing potential therapeutic avenues for various genetic diseases.
This novel strategy was tested in with genetic diseases, such as aplastic anemia and pulmonary fibrosis, which have known mutations in the telomerase gene. The researchers believe that the approach they took in this new study may help combat the damage caused to patients by telomerase deficiency.
“One of the processes associated with aging is a progressive shortening of telomeres, DNA-protecting structures at the ends of chromosomes, like the plastic tips on shoelaces,” explained co-author Rodrigo Calado, M.D., Ph.D., professor at the University of São Paulo's Ribeirão Preto Medical School (FMRP-USP). “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.”
Scientists often use telomere length as a laboratory measure of a cell's age. Interestingly, 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.”
Embryonically, where tissues are still in their formative stages, 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,” Dr. Calado noted. “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.”
Previous work done by Dr. Calado and his colleagues showed that androgens, which are converted into estrogens in humans, bound to female hormone receptors in the telomerase gene promoter region and thereby stimulated 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,” Dr. Calado remarked.
The findings from this study were published recently in The New England Journal of Medicine in an article entitled “Danazol Treatment for Telomere Diseases.”
Instead of estrogen, the researchers treated the patients with the androgen danazol, a synthetic male hormone, 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. Treatment with this steroid was tested for 2 years in 27 patients with aplastic anemia owing to telomerase gene mutations.
“In a healthy adult, telomere length varies from 7000 to 9000 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,” stated Dr. Calado. “In the patients who received danazol, telomere length increased by 386 base pairs on average over 2 years.”
Additionally, the researchers found that 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.
“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,” Dr. Calado said.
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.
While the results of the current 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 such treatment would surpass the risks in healthy people, especially if the treatment involves the use of sex hormones.