Growth Hormone: Fountain of Youth or Early Killer?

A small population of dwarves in rural Ecuador could hold the answer.

Growth hormones: When growth hormone binds to its receptor, shown here (top), it activates a number of cellular pathways involved in growth and metabolism. When people have a nonfunctional version of the receptor--inactivating mutations are shown here in dark blue--they develop Laron syndrome, a type of dwarfism. Valter 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 (bottom)

Growth hormone holds a conflicted status in the world of life extension. Some believe it turns back the clock, with evidence from humans suggesting that hormone treatment reduces fat and boosts muscle. But animal studies show the opposite: mice without growth hormone live significantly longer and are protected against cancer, one of the most deadly diseases of aging.

Valter Longo, a scientist at the University of Southern California, in Los Angeles, hopes to untangle this conundrum by studying an unusual group of people in Ecuador: those with a genetic mutation that renders them insensitive to growth hormone. "They are the largest population in the world that is growth-hormone deficient," says Longo. Studies of the group could provide a valuable window into whether growth-hormone depletion could, in fact, be used to extend longevity. The study could also shed light on how to develop drugs against the diseases of aging without introducing unintended side effects.

Growth hormone is a crucial protein produced by the pituitary that directs growth and cell division. People who lack the hormone or the ability to respond to it are extremely short, while those whose hormone levels dip in middle age, such as after damage to the pituitary, have an increased risk of cardiovascular disease. In mice, however, deficiency of the hormone seems to be beneficial. "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."

The group Longo plans to study lives in the rural Loja province in the southern portion of Ecuador. These isolated mountain communities have a high rate of an otherwise rare condition known as Laron dwarfism. People with the condition lack a functioning version of the receptor that binds to growth hormone.They are small and obese, but little data exists on their longevity.

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.

To try to determine how the hormone impacts diseases of aging, Longo plans to compare rates of cancer, heart disease, and diabetes, as well as longevity data, in those with one or two copies of the gene and their unaffected relatives. Those who carry one functioning copy of the growth-hormone receptor appear normal; if they are protected against cancer and do not suffer from obesity and heart disease, they may represent a happy medium of growth-hormone exposure. So far, the scientist has genotyped about 300 people--100 with two copies of the mutation, and 200 relatives and controls.

"If blocking growth hormone is associated with an improvement or decreased incidence of cancer, there are tools that we have as physicians to address that," says Pinchas Cohen, a pediatric endocrinologist at the University of California, Los Angeles, who has treated children with Laron dwarfism. Drugs that inhibit secretion of the hormone or block its action already exist. And drug companies are now testing blockers of a molecule that acts downstream of growth hormone, called 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.

Not everyone is optimistic that limiting growth hormone in people will have the same effects it does in mice. "Growth hormone in humans is different than that of most mammals," says Austad. It has a broader mechanism of action and appears to have evolved rapidly since we diverged from other mammalian ancestors. "No one knows why," says Austad, "but something has happened to make growth hormone very different in humans."

http://www.technologyreview.com/Biotech/20096/