Why is it so difficult to create anti-aging drugs?

The human need to believe in eternal life, or at least to look younger for longer is reflected in the world’s most successful religions and on the shelves of drugstores. Aging remains shrouded in mystery, but scientific progress over the last few decades has identified various biological processes that help to explain the phenomenon. And the findings have once again fed the age-old desire to do something about it. Among the signs of aging is telomere attrition. The length of these protective sheaths at the ends of the chromosomes (where we store the information that tells our bodies how to stay alive) is related to the number of times a cell can divide to make daughter cells. Having telomeres that are too short has been linked to accelerated aging and diseases such as pulmonary fibrosis.

Some companies, such as Telomere Therapeutics, led by María Blasco, from the Spanish National Cancer Research Center, and Fàtima Bosch, from the Autonomous University of Barcelona, want to develop treatments to activate the production of telomerase (an enzyme that repairs the wear and tear on the sheaths) and treat the ailments that occur when the telomeres are too short. Other companies, such as BioViva in the United States, are proposing similar therapies to slow down aging in healthy people, and there are already creams based on telomerase that promise to remove wrinkles. The view of telomerase as a magic potion against aging — a process in which a large number of interacting and sometimes counteracting mechanisms operate — has been widely criticized. Although telomeres that are too short cause predisposition to some diseases, having excessively long telomeres has been linked to an increased risk of developing certain tumors.

A few days ago, the medical journal The New England Journal of Medicine published a study that has reignited the debate on telomeres’ role in aging. The authors, led by Mary Armanios, director of the Johns Hopkins University Telomere Center in Baltimore, Maryland, followed 17 people with a mutation in the POT1 gene for two years. This characteristic means that, in most cases, their telomeres do not lose length with each cell division — as is the case with most cells — and so they are excessively long. The researchers observed that this characteristic was associated with a blood disease (clonal hematopoiesis), which favors the proliferation of cell mutations and, in some cases, of various types of tumors. Four of the patients studied by Armanios’ team died of cancer and others were more prone to the disease.

“One of the conclusions of this paper is that long telomeres maintain mutations. We develop most of the mutations when we are developing and it is the long telomeres that allow them to survive long enough to cause problems,” explains Armanios. “I think telomeres don’t explain all forms of aging, only one subtype, and that’s the type of aging that has to do with clockwork mechanisms, where cells divide too many times or too few times,” she continues. In cases of low partitioning, pulmonary or immune system diseases would appear, and excess partitioning would facilitate the growth of cancerous tumors. “My interpretation is that in humans both extremes are bad and cause disease, albeit of different types,” she adds.

Long or damaged

María Blasco disagrees with the interpretation of the results and attributes the increased risk of cancer to the POT1 mutation, which belongs to a group of proteins, known as shelterins, that protect telomeres. “In my group and others we have shown that when this protein is missing or defective, telomeres are longer, but they are dysfunctional,” she notes. She recalls a paper she co-authored in 2013 (published in the scientific journal, Nature Genetics) and carried out as part of the Chronic Lymphocytic Leukemia genome study project, in which they already identified POT1 mutations as a risk factor in the onset of cancer. For the researcher, the particularity of the telomeres studied, which came from of a mutation, “does not allow us to conclude that a long telomere is bad.”

Another point of view is advocated by Titia de Lange, who is the director of the Anderson Cancer Research Center at Rockefeller University in New York and the person responsible for coining the term shelterin. Following the publication of the link between POT1 mutations and long telomeres, “there was a lot of follow-up work in the years that followed because it was unclear whether POT1 mutations simply produced the long telomere phenotype or did something else to instigate cancer,” De Lange says. For the scientist, recent work from her laboratory and that of Dirk Hockemeyer at the University of California at Berkeley, California, suggests that “POT1 and similar TIN2 mutations produce cancer because the patients have long telomeres. We have shown that there is nothing wrong with telomeres beyond being long,” she adds. “We and other groups have demonstrated that [in cases of normal length] lengthening telomeres is not desirable and that telomere shortening is a good thing that protects us from cancer,” she asserts.

Regarding the application of telomerase as a treatment, Blasco points out that “there is currently no research on activating telomerase in order to have longer telomeres and live longer. The interest is in activating telomerase to combat diseases associated with short telomeres, such as pulmonary fibrosis,” she explains. Luis Batista, of the Center for Regenerative Medicine at Washington University in St. Louis, Missouri, agrees on the usefulness of these treatments “for extremely short telomeres, because in those cases the individual’s tissues can be revitalized,” but considers that the therapies to lengthen telomeres “that can be found on the internet do not make any sense from the point of view of normal physiological aging, which is what most of us have. From what results like Armanios’ show, it can even be dangerous,” he adds.

The gray hair paradox

The complexity of telomere length as a therapeutic target has been observed in studies such as the one led by Nilesh Samani, of the University of Leicester (U.K.), in which almost half a million participants in the UK Biobank were analyzed. In that work, published in Nature Genetics in 2021, an increased risk of cardiovascular or respiratory diseases was observed when telomeres were shorter and of several types of cancer when they were longer. This is possibly because long telomeres allow cells to divide more and increase the likelihood of harmful mutations. The authors also recognized that, although different diseases are associated with longer or shorter telomeres, people with the shortest telomeres at age 40 lived about 2.5 years less on average, compared to 10 years less in people who smoke for many years or 6 years less in people with diabetes.

Mary Armanios points out the paradoxes she observed in some of her patients. “Those who had extraordinarily long telomeres, didn’t get gray hair, and they looked young, but at the same time they developed cancer of the melanocytes, the cells that keep their hair from turning gray. It’s as if the cosmetic changes of aging that we don’t like, prevent us from developing some types of cancer,” she says. In the researcher’s opinion, “lengthening the telomeres is possible, and you are going to make the cells live longer. And it is possible that the individual will live longer, but it is going to do so with these tumors,” she continues. “It’s not about long telomeres being a good thing and short telomeres being a bad thing, the good thing is probably in the middle. Perhaps we should accept that evolution generated these constraints to protect us from developing too many tumors as we age,” she concludes.

Despite the appeal of the fountains of eternal youth that abound in mythology, and treatments that attempt to combat the passage of time, Armanios, like other researchers, is doubtful about the possibility of acting in a meaningful way on a biological mechanism that, distressing as it is, seems very well programmed. While acknowledging the potential of some treatments for accelerated aging, she considers it unlikely that a drug that will add 20 years to a normal life expectancy will be developed. However, she warns that we sometimes forget one aspect where there is enormous room for improvement: the socioeconomic gap. In countries like Spain, there can be a difference of more than a decade in life expectancy between rich and poor, a problem that can be addressed without the side effects of manipulating telomeres.

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