Missing link in hunt for long life without disease

THEY are much smaller than average, less than three and a half feet tall, and have a rare condition called Laron syndrome. They are probably the descendants of conversos, Sephardic Jews from Iberia forced to convert to Christianity in the 1490s but still driven out by the Inquisition.

Living in a remote Ecuadorean community, they are also almost free of two age-related diseases, cancer and diabetes. Now biologists believe they may throw light on longevity and ways to increase it.

The group of 99 villagers with Laron syndrome - a type of dwarfism - has been studied by Dr Jaime Guevara-Aguirre, an Ecuadorean physician and diabetes specialist. He discovered them when travelling on horseback to a roadless mountain village. Most such villages are inhabited by native people, but these were Europeans, with Spanish surnames typical of conversos.

As Guevara-Aguirre accumulated health data, he noticed a remarkable pattern: though cancer was frequent among people who did not have the Laron mutation, those who did have it almost never got cancer. And they never developed diabetes, even though many were obese, a key risk factor.

"I discovered the population in 1987," Guevara-Aguirre said. "In 1994, I noticed these patients were not having cancer, compared with their relatives. People told me they are too few people to make any assumption. People said, 'You have to wait ten years,' so I waited. No one believed me until I got to Valter Longo in 2005."

Longo, a researcher on ageing at the University of Southern California, saw the patients as providing an opportunity to explore in people the genetic mutations that researchers had found could make laboratory animals live longer.

The Laron patients, many of whom have families, have a mutation in the gene that makes the receptor for growth hormone. The receptor is a protein embedded in the membrane of cells. Its outside region is recognised by growth hormone circulating through the body; the inside region sends signals through the cell when growth hormone triggers the receptor.

The Laron patients' mutation means their growth hormone receptor lacks the last eight units of its exterior region, so it cannot react to growth hormone. In normal children, growth hormone makes the cells of the liver churn out another hormone, called insulin-like growth factor, or IGF-1, and this makes the children grow. If the Laron patients are given doses of IGF-1 before puberty, they can grow to fairly normal height.

This is where the physiology of the Laron patients links up with the longevity studies that researchers have been pursuing with lab animals. IGF-1 is part of signalling pathway that exists in the lab roundworm as well as in people. The gene that makes the receptor for IGF-1 in the roundworm is called DAF-2. And worms in which this gene is knocked out live twice as long as normal.

The Laron patients have the equivalent defect - their cells make very little IGF-1, so very little IGF-1 signalling occurs. So the Laron patients might be expected to live much longer.

Longo said he believed that having very low levels of IGF-1 was the critical feature of the Laron patients' freedom from age-related diseases. In collaboration with Guevara-Aguirre, he exposed human cells in a lab dish to serum from the Laron patients. The cells were then damaged with a chemical that disrupts their DNA.

The Laron serum had two significant effects.

First, the serum protected the cells from genetic damage. Second, it spurred damaged cells to destroy themselves, a mechanism the body uses to prevent them becoming cancerous. Both effects were reversed when small amounts of IGF-1 were added.

Andrzej Bartke, a gerontologist at Southern Illinois University, said the new result was "very important." "This fits in with what we are learning from studies in animals about the relationship of growth hormone to ageing, because both cancer and diabetes are related to ageing," Bartke said.

The longest-lived mouse is one studied by Bartke. It had a defect in its growth hormone receptor gene, just as do the Laron patients. "It missed its fifth birthday by a week," he said. The mouse lived twice as long as usual and won Bartke a prize presented by the Methuselah Foundation (which rewards developments in life-extension therapies) in 2003.

Guevara-Aguirre said he had been struggling to get sufficient IGF-1 to treat 30 of his patients before they reached puberty, at which point it will be too late. He said his group of Laron patients, the largest recorded, had provided essential data for drug companies making IGF-1, and criticised the companies for not providing the drug for his patients.

Geneticists concede that the Laron patients may help unlock the key to longer lives. Dr Harry Ostrer, a geneticist at New York University exploring the Laron patients' Sephardic ancestry, said that he had seen several of Guevara-Aguirre's patients in Quito, Ecuador's capital, and that they were "remarkably youthful in appearance".