Genetic solution to cancer, diabetes?

Can a gene that causes dwarfism also confer major health benefits? Perhaps, according to a new study showing that a group of extremely short people in Ecuador get no diabetes, even though they are unusually obese.

The 22-year study of people living in villages on the slopes of the Andes mountains also found just one case of cancer in the 99 patients it tracked, many fewer than among non-dwarf relatives.

The absence of two of the worst diseases of aging was strong evidence that the mutation that causes what’s called “Laron syndrome” has an upside, says Valter Longo, a gerontologist at the University of Southern California, and the senior author on the new study. “If you talk to anybody in the field, there is no way you can have a population with increased obesity and no diabetes. What was particularly strange was having zero deaths from cancer with 22 years of direct monitoring.”

Unfortunately, the subjects did not outlive the comparison group of relatives, due to large numbers of accidents and other alcohol-related problems.

The Laron’s patients are descendants of “Conversos,” Jews who were forcibly converted to Catholicism in Spain after 1492, and who emigrated to Latin America to escape continued persecution. Laron’s syndrome is also found in Israel and several other Middle-eastern countries.

The root of Laron’s syndrome, AKA growth hormone receptor deficiency, is a genetic mutation that disables the growth-hormone receptor, says Arlan Rosenbloom, a professor emeritus of pediatric endocrinology at the University of Florida who has long studied the Ecuadorian group but was not involved with the current report. “Growth hormone binds to its receptor on cell surfaces to stimulate production of insulin like growth factor-I (IGF-I) which is the real ‘growth hormone,'” Rosenbloom says. “Failure of the growth-hormone receptor cuts growth after birth by 50 percent. The Ecuadorians with this condition, 99 living individuals, comprise upwards of one-third of all individuals in the world with growth-hormone receptor deficiency.”

Image: Mikael Häggström

Growth hormone, secreted by the pituitary gland, travels to the liver, where it stimulates the formation of insulin-like growth factor 1, which stimulates bone growth.

The genetic angle

The new comparison of genetic differences between Laron patients and their non-dwarf relatives emerged from what Rosenbloom calls “spectacular epidemiological observations” by first author Jaime Guevara-Aguirre, an Ecuadorian endocrinologist who treats the Laron’s patients.

Working with Rafael de Cabo, a collaborator at the National Institute on Aging, Priya Balasubramanian from Longo’s research group exposed human epithelial cells, where most human cancers originate, to blood serum from control and Laron subjects. Serum is the cell-free portion of blood. “We wanted to know how this would affect the expression of dozens of genes,” says Longo, who studies cellular changes in aging.

The springboard of modern aging research is caloric restriction, because a diet with roughly 65 percent of normal calories is the only life-extension technique that works in a vast range of organisms. Although a similar group of protective genes activate under caloric restriction in yeast, fruitflies and mice, “We did not expect that a lot of the genes we study in yeast would come out as the most affected” in patients with a broken growth-hormone receptor, Longo says. “Serum from the Laron patients caused changes that we and others have shown to be highly protective in simple systems [like yeast]. We hoped for this but never really expected that many of the same genes would be coming up.”

At the molecular level, a key mechanism of aging is “oxidative stress,” damage to proteins and DNA caused by reactive molecules and fragments containing oxygen. When the researchers exposed human cells to the oxidant hydrogen peroxide, far fewer DNA breaks appeared in cells bathed in serum from the Laron patients, suggesting that they were protected against cancer.

The study found a second critical difference: When the DNA was damaged, cells in Laron serum were much more likely to commit suicide through apoptosis. Because apoptosis is a major obstacle to cancer, this suggested that cells in a Laron patient that had started on the path toward cancer would be more likely to kill themselves before going rogue.

Combined, the two phenomenon seem to explain why during the 22-year study only one of the Laron’s patients being tracked had a cancer, which was successfully treated. About 17 percent of their normal-height relatives had cancer during the same period.

Growing more confident

The study illuminates the role of insulin-like growth factor-1 (IGF-1), a growth hormone that, while required during development, may cause problems later on. “Large population studies show that people with the highest levels of IGF-I are at increased risk for certain types of cancer,” says Rosenbloom.

Longo notes that the effects of IGF-1 may depend on whether it is formed in an individual organ or distributed in blood. “Our hypothesis is that we do not need a ton of circulating IGF-1,” Longo says. Laron patients have between 0 and 10 percent of the normal level of IGF-1, “but they are fine, several made it into their 80s.”

The Ecuadorian study was more evidence that IGF-1 formation requires a functioning growth-hormone system. A drug that blocks the growth-hormone receptor has been approved for treating acromegaly, or gigantism, which is caused by excessive production of growth hormone.

You don’t have to be a hypochondriac to wonder if such a drug could prevent cancer and diabetes in adults, but the new study shows correlation, not proof, and Longo advocates a more modest first step in clinical trials. Return to caloric restriction for a moment: Studies in mice show that fasting reduces IGF-1 and protects healthy cells — but not tumor cells — from damage during chemotherapy, and some cancer patients have begun fasting to reduce collateral damage during chemo. “I think that soon enough, we will start with a clinical trial of this growth-hormone receptor antagonist to protect cancer patients against chemotherapy toxicity,” Longo says.

The new study is further proof, that, up and down the line from yeast to mice to people, similar “conserved” biochemical mechanisms influence aging, cancer and diabetes, Longo says. “The conservation hypothesis is something I am very convinced of, but I did not expect what we saw. Maybe we would see major reductions in cancer and insulin resistance [a marker of diabetes], but to see not one case of diabetes, not one cancer death, and to see the genetic matches with the simple systems that we study, that was as good as we could hope for.”