A 22-year study of an extended family in Ecuador suggests that insensitivity to human growth hormone, which causes a condition called Laron dwarfism, also has health benefits. Researchers found that none of the 100 affected people in the study suffered from diabetes and only one had a non-lethal case of cancer. In comparison, five percent of 1600 unaffected relatives studied over the same time period were diagnosed with diabetes and 17 percent with cancer, rates similar to those of the broader Ecuadorian population.
The disorder is caused by a mutation in the receptor for human growth hormone, which renders people with two copies insensitive to the hormone. Researchers hope the findings, published today in Science Translational Medicine, will aid in the development of new drugs to help combat or prevent some of the diseases of aging. Drugs that block human growth hormone are already on the market to treat a condition related to gigantism.
Growth hormone is a crucial protein produced by the pituitary that directs growth and cell division. While some people think that supplements of human growth hormone (HGH) can combat aging—Sylvester Stalone was caught with HGH in Australia several years ago–animal studies suggest the opposite; mice without growth hormone live significantly longer and are protected against cancer, one of the most deadly diseases of aging.
As I noted in a previous story describing the project;
“In the mouse, the effect is major and striking,” says Andrzej Bartke, a biologist at Southern Illinois University in Springfield, who is not involved in the project. “They seem protected from cancer and appear to have delayed aging by various measures. But there is almost no evidence that growth-hormone deficiency would extend life in humans.”
Walter Longo, a biologist who studies aging at the University of Southern California, is pictured (bottom) with a person with Laron dwarfism. Longo plans to study how this mutation affects life span and the diseases of aging. Credit: T. Blundell & N. Campillo, Wellcome Images (top), Valter Longo
The new study, conducted by cell biologist Valter Longo of the University of Southern California and Ecuadorian endocrinologist Jaime Guevara-Aguirre, supports the animal research. According to a press release from the journal:
To pinpoint the molecular causes for this remarkable lack of disease, the researchers performed gene expression analyses of thousands of genes from blood samples of family members. They found that family members with the [growth hormone receptor] gene mutation have lower amounts of Insulin-like Growth Factor 1 or IGF-I, as well as lower insulin concentrations and higher insulin sensitivity. And when stressed, their cells tend to self-destruct rather than accumulate DNA damage. All of these features are known to promote longevity in lower organisms. Although it’s difficult to prove that major reductions in IGF-I and insulin concentrations are responsible for the lack of cancer and diabetes in this Ecuadorian family, the findings coincide with similar observations in lower organisms like yeast, worms and mice. In yeast, mutations in growth genes protect against age-related genomic havoc, while mutations in insulin-related signaling pathways increase life span and reduce abnormal cell proliferation in worms.
Drug companies are currently testing blockers of a molecule that acts downstream of IGF-1 as a treatment for cancer. If IGF-1 works, it’s not yet clear if the most effective intervention will be as a preventative measure, perhaps targeting families with a history of cancer, or if growth-hormone or IGF-1 depletion could be used as a cancer treatment. According to a press release from the university, Longo’s team would initially seek approval for a clinical trial to test HGH targeting drugs for the protection of patients undergoing chemotherapy.
The family in the study, identified in the 1990s, is centered in the Loja province in the southern portion of Ecuador, an isolated mountain region where intermarriage is common. The family descends from Spanish Jews thought to have emigrated after the Inquisition. (The mutation was originally identified in a small number of people in Israel.) People with the condition are small and obese, but little was known about their longevity.
According to the new study, people with the mutations don’t live longer. In fact, they are more likely to die from from substance abuse and accidents. In addition, people with the mutation suffer other health problems beyond short stature. As I noted in the previous story,
Children with the condition seem more susceptible to pneumonia and diarrhea, common scourges of poor rural communities, and they die at twice the rate of their unaffected siblings. Those who survive to adulthood typically have high cholesterol and triglycerides, risk factors for heart disease. Some die of heart disease, an uncommon occurrence in rural Ecuador, but preliminary reports suggest that Laron dwarves are protected from artherosclerosis, arterial hardening that can lead to heart attack. Adding to the puzzle is anecdotal evidence suggesting that they don’t get cancer or type 2 diabetes. “It’s a balance: if you turn down risk of cancer, you might turn up risk of heart disease,” says Steven N. Austad, a biologist at the University of Texas Health Sciences Center, in San Antonio, who is not involved in the project.