For the past 22 years Jaime Guevara-Aguirre has served as the de facto physician for a truly unique community in Ecuador. His patients stand on average 1.2 meters tall, a result of a rare genetic disorder known as Laron syndrome. Of the approximately 300 people in the world known to have the condition, a third reside in the remote mountainside villages of southern Ecuador. Another remarkable fact about Guevara-Aguirre’s patients: virtually none of them suffer from cancer or diabetes.
The same genetic mutation—an error in the growth hormone receptor (GHR) gene—that causes unusually small stature in Laron syndrome also confers seeming immunity from two of the most common diseases that plague mankind. Since 1988 no cases of diabetes and only one case of nonlethal cancer have been diagnosed in 99 Laron's subjects followed by Guevara-Aguirre. In comparison, fellow villagers without the GHR mutation had a diabetes diagnosis rate of 5 percent and a cancer diagnosis rate of 17 percent over the study period.
GHR-deficient individuals are insensitive to growth hormone and also have abnormally low levels of insulinlike growth factor 1 (IGF1), a hormone that promotes cell proliferation and inhibits programmed cell death. More than two decades of clinical observations by Guevara-Aguirre's team are now supported by molecular studies linking low levels of IGF1 to cellular protection against cancer and other age-related diseases.
"If we can establish that IGF1 is a risk factor for cancer, then you could imagine that doctors could prescribe IGF1-lowering drugs as we are now doing for cholesterol with statins," says Valter Longo of the University of Southern California's Programs in Biomedical and Biological Sciences, who collaborated with Guevara-Aguirre on a study of the Ecuadorian community published February 16 in Science Translational Medicine.
To investigate the cellular responses to IGF1, researchers bathed isolated human cells in blood serum taken from Laron subjects and from relatives without the mutation. When exposed to a toxin, cells bathed in Laron serum suffered fewer DNA breaks, suggesting that the lack of IGF1 protects against oxidative DNA damage. The protection disappeared when IGF1 was artificially added to the Laron serum.
"I can say that we both came to the same conclusion from different routes—Valter from the basic, and I from the clinical sciences"—says Guevara-Aguirre, who is the medical director at the Institute of Endocrinology, Metabolism and Reproduction in Quito, Ecuador.
The two research teams began their collaboration in 2005. "I realized that nobody was working in humans that had a defect in GHR. We were working on all kinds of model systems," Longo says.
Previous work on model organisms had suggested the role of IGF1 in cancer prevention and aging. Dwarf mice with the same GHR mutation have low cancer rates, increased insulin sensitivity that protects against diabetes, and extended life span. But it was impossible to study IGF1 in humans in the same way due to the extreme rarity of the naturally occurring GHR mutation.
Meanwhile, Guevara-Aguirre had been studying the distorted body composition in the Laron subjects, but was struck by their unusual resistance to common diseases. "In 1988 I noticed that these patients had no diabetes despite being obese. In 1994 I also noticed they had no cancer. A few years later we documented they were insulin sensitive. These facts were fascinating to me," he says. When Longo heard about Guevara-Aguirre's work and his close relationship with such a large population of Laron's subjects, he realized that it could be the "perfect natural experiment."
The study represents the first time that the GHR-deficiency mutation has been studied in a human population. Unlike dwarf mice, however, people with Laron syndrome do not seem to experience increased longevity. The effect on life span may have been obscured in this study by the unusually high number of accidents and alcohol-related deaths seen in the Laron subjects. "Being three-and-a-half feet tall, accidents just happen," Longo says.
Despite the extreme rarity of Laron syndrome, the study findings have important implications for the general population. It is already known that IGF1 can be modulated by diet—specifically, that protein restriction lowers IGF1 levels.
"All the data is coming together now," says Luigi Fontana who studies nutrition and aging at Washington University in Saint Louis School of Medicine and was not involved in the study. "Put together all the pieces of the puzzle and you see that yes, IGF1 is an important determinant of cancer." According to Fontana, greater protein intake and higher IGF1 levels contribute to the increasing cancer incidence in recent generations; a similar trend is seen in immigrant populations that move from Eastern to Western diets.
However, Longo cautions, "people shouldn't make up their own diets to try to extend their life. If you don't have a clear disclaimer, you will be amazed at what people do."
Longo suspects the IGF1 pathway may be involved in the great majority of the diseases of aging, including osteoporosis, Alzheimer's disease and cognitive decline. He hopes to extend the current study but acknowledges that the lower prevalence of these conditions, compared with that of cancer and diabetes, make them more difficult to study in a population of limited size.