The study of Ecuadorian families with a rare disease known as Laron syndrome has just shown that a genetic mutation protects them from cardiovascular diseases. Those responsible for the work believe that it is possible to search for a drug or a diet that mimics the beneficial effects observed to combat diseases associated with aging, such as cancer, in the general population.
In 1987, Ecuadorian endocrinologist Jaime Guevara-Aguirre began treating people with Laron syndrome who lived in isolated towns in the provinces of Loja and El Oro, in the south of the country, near the border with Peru. The disease is characterized by a mutation in the growth hormone receptor gene that causes dwarfism. A wearer does not exceed one and a half meters in height. The cause is a mutation of a single biochemical letter—a G instead of an A—in the very long sequence of 3 billion letters that makes up the human genome. In these communities, endogamy is common, which has favored the spread of the syndrome. Even today, the inhabitants of these towns continue to have children without knowing if they will be born with Laron or not. In the family photos of these communities, affected parents are seen with their children of about 10 years old who are already taller than them.
In a teleconference from Quito, Guevara-Aguirre apologizes in case communication is interrupted due to the blackouts that afflict the country, plunged into a spiral of violence and instability. “In 1987 it took two days to get to these towns in my father's 4×4, and some of them you had to walk two or three more hours. It was a very remote area, but the patients were fascinating,” recalls Guevara-Aguirre, from the Universidad San Francisco de Quito. Since then he has diagnosed about 100 affected people, approximately a third of all those in the world.
After two decades of follow-up, the doctor observed an enigmatic pattern: there was hardly any cancer or diabetes in Laron's carriers, while their apparently healthy relatives suffered from these ailments with the same frequency as the rest of Ecuadorians. The doctor postulated that Laron's mutation protects against diseases related to aging. The topic caught the attention of biochemist Valter Longo, a researcher at the University of Southern California focused on the search for diets capable of stopping chronic diseases.
In 2011 they showed that those affected by Laron produced less IGF-1, a protein essential for childhood growth but which in adults also promotes uncontrolled cancer cell proliferation. In laboratory studies, mice with low levels of this protein live up to 40% longer, suffer fewer tumors, and appear smaller than normal.
In 2017, the pair of researchers published another study that pointed out that this mutation also protects against neurodegenerative ailments. Although very few affected people live beyond 80 years of age, among those identified there were no cases of Alzheimer's no dementia. While many of the relatives without the mutation suffered and died from diseases related to aging, those affected by the syndrome died mainly from accidents or alcoholism, very common in these Andean communities.
In their new work, the researchers postulate that the Laron mutation also has a protective effect against cardiovascular diseases. They have studied 21 men with the syndrome and 23 unaffected relatives. Carriers have lower glucose levels and blood pressure. Despite showing high levels of “bad” LDL cholesterol, they have far fewer arteriosclerosis plaques, according to the study, published in the journal. Specialized magazine Med.
“This is the most important study of all,” Longo emphasizes. “Skeptics maintained that the most common cause of death in these people was heart problems, but we showed that this is not the case,” he adds. Many of the patients studied are overweight or obese and lead a poor lifestyle, with high consumption of tobacco and alcohol. “The worst thing is that we see that some of them understand that they can do whatever they want because they are protected, which is obviously not the case,” highlights the Italian-American biochemist, who has visited these villages in Ecuador “dozens of times.”
Longo highlights that diets that mimic fasting, which he himself has designed, lower IGF-1 levels in the circulation, the supposed cause of the beneficial effects observed both in animals and in people with Laron. Another of the authors of the work, John Kopchick, from the University of Ohio (United States), has shown that several molecules that block the growth hormone receptor slow tumor progression in mice and in human breast cancer cells, and improve the effectiveness of conventional treatments. One of these molecules is Pegvisomant, an already approved drug manufactured by the multinational Pfizer to treat acromegaly, a hormonal imbalance that causes excessive growth of the face and extremities.
Israeli doctor Zvi Laron discovered the syndrome in 1966 in highly consanguineous Jewish families from Yemen. In 2013, a genetic study pointed out that this mutation probably originates from Spanish and Portuguese Sephardic Jews who fled the Inquisition in the 15th century and founded small communities in Ecuador, Chile, and Brazil. There are 17 different mutations that cause Laron syndrome, and one of them reached America, explains the scientist, professor emeritus at Tel Aviv University. In recent years, he has published several studies focused on how to replicate the cancer-protective effects he sees in these patients. The scientist believes that the results seen in Ecuador cannot be generalized. “In our cohort of 76 individuals followed for many years, we have seen that the majority of older and obese patients develop insulin resistance and three men and eight women suffered from diabetes,” but only one of them has the same mutation. than Ecuadorians, he details. His next scientific goal is to calculate how many people actually suffer from this ailment around the world. “There are probably more than 500, but in many countries they are never diagnosed,” he highlights on the phone from Tel Aviv.
Laron syndrome is recessive, which means that you have to inherit two mutated copies of the gene, one from the father and one from the mother, to suffer from it. It is possible for one person with the syndrome to have healthy children, and it is also possible for two normal-looking people to carry the mutation and have children with the syndrome. “It's a genetic lottery” that is amplified due to inbreeding, admits Guevara-Aguirre.
The doctor has shown that dwarfism can be alleviated by administering recombinant IGF-1 protein from an early age. Furthermore, since 1992, he has tried to establish a “massive” genetic diagnosis system that would allow these inhabitants to know if their partners are carriers of the mutation, but this has not yet been done. “It is an easy and cheap intervention, but it has not materialized due to the ignorance of the authorities,” she says.
Guevara-Aguirre's goal now is to determine whether carriers of the mutation live longer than their siblings and other relatives. “My feeling is yes, but it has to be proven. The problem is that this area is controlled by the narco-guerrilla,” she laments.
CSIC researcher Alejandro Martín-Montalvo collaborated with Longo and Guevara-Aguirre in their study on Laron and cancer in 2011. The researcher considers that “this new work is an advance, as it shows that these people are not predisposed to failures cardiac as was thought until now.” “In addition, it opens a possible new line of research on how to transfer these benefits to the general population,” he adds.
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