The Link Between Laron Syndrome And Increased Longevity And Cancer Decrease

While I was doing research on Larons Syndrome, I found out about the startling fact that people who have Laron Syndrome which is a lack of the growth hormone receptors to work, seem to have extremely low rates of cancer and diabetes, as well as increase in their lifespan. I don’t want to talk too much about the subject but will let the writers who wrote articles about this phenomena speak.

From the New York Times (source HERE)…

Ecuadorean Villagers May Hold Secret to Longevity

By NICHOLAS WADE
Published: February 16, 2011
  • People living in remote villages in Ecuador have a mutation that some biologists say may throw light on human longevity and ways to increase it.
A 32-year-old community leader and artist who has the rare dwarfism condition, with his bride, 17.

The villagers are very small, generally less than three and a half feet tall, and have a rare condition known as Laron syndrome or Laron-type dwarfism. They are probably the descendants of conversos, Sephardic Jews from Spain and Portugal who were forced to convert to Christianity in the 1490s but were nonetheless persecuted in the Inquisition. They are also almost completely free of two age-related diseases, cancer and diabetes.

A group of 99 villagers with Laron syndrome has been studied for 24 years by Dr. Jaime Guevara-Aguirre, an Ecuadorean physician and diabetes specialist. He discovered them when traveling on horseback to a roadless mountain village. Most such villages are inhabited by Indians, but these were Europeans, with Spanish surnames typical of conversos.

As Dr. Guevara-Aguirre accumulated health data on his patients, 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, which often brings on the condition.

“I discovered the population in 1987,” Dr. Guevara-Aguirre said in an interview from Ecuador. “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 10 years,’ so I waited. No one believed me until I got to Valter Longo in 2005.”

Valter D. Longo, a researcher on aging 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 much longer than usual.

The Laron patients 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 recognized 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 that 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 insulinlike growth factor, or IGF-1, and this hormone 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 laboratory animals. IGF-1 is part of an ancient signaling pathway that exists in the laboratory 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 signaling takes place, just as in the DAF-2-ablated worms. So the Laron patients might be expected to live much longer.

Because of their striking freedom from cancer and diabetes, they probably could live much longer if they did not have a much higher than usual death rate from causes unrelated to age, like alcoholism and accidents.

Dr. 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 Dr. Guevara-Aguirre, he exposed human cells growing in a laboratory 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, the two physicians reported on Wednesday in Science Translational Medicine.

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

Dr. Longo said that some level of IGF-1 was necessary to protect against heart disease, but that lowering the level might be beneficial. A drug that does this is already on the market for treatment of acromegaly, a thickening of the bones caused by excessive growth hormone. “Our underlying hypothesis is that this drug would prolong life span,” Dr. Longo said. He said he was not taking the drug, called pegvisomant or Somavert, which is very hard to obtain.

A strain of mice bred by John Kopchick of Ohio University has a defect in the growth hormone receptor gene, just as do the Laron patients, and lives 40 percent longer than usual.

Dr. Longo said that his report had first been submitted to Science, a better-known journal, which turned down the paper because of an adverse report from one reviewer.

Andrzej Bartke, a gerontology expert at Southern Illinois University, said that the new result was “very important” and that the authors had done a fine job in following the patients and generating high-quality data. “This fits in with what we are learning from studies in animals about the relationship of growth hormone to aging, because both cancer and diabetes are related to aging,” Dr. Bartke said.

The longest-lived mouse on record is one studied by Dr. 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 Dr. Bartke a prize presented by the Methuselah Foundation (which rewards developments in life-extension therapies) in 2003.

Dr. 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 in the world, had provided essential data for drug companies making IGF-1, and he chided the companies for not reciprocating by providing the drug for his patients.

Dr. Arlan Rosenbloom, a pediatric endocrinologist at the University of Florida who has worked with Dr. Guevara-Aguirre, took a similar position. “Considering that the drug companies needed the initial studies to determine dosage and efficacy, it seems ironic that we should have so much difficulty getting the drug,” he said.

Ownership of the drug has passed through several companies’ hands, so any initial obligation may have been weakened. Dr. Guevara-Aguirre also said he believed that the government of Ecuador should do more to help get the drug for his patients.

Dr. Harry Ostrer, a geneticist at New York University who is exploring the Laron patients’ degree of Sephardic ancestry, said that he had seen several of Dr. Guevara-Aguirre’s patients in Quito, Ecuador’s capital, and that they were “remarkably youthful in appearance.”

A version of this article appeared in print on February 17, 2011, on page A6 of the New York edition.

From the Magazine Scientific American website (source HERE)…

Defective Growth Gene in Rare Dwarfism Disorder Stunts Cancer and Diabetes

A long-term study shows that people with Laron syndrome, a genetically based form of dwarfism, almost never succumb to cancer or diabetes

By Nina Bai

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 thegrowth 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 cholesterolwith 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.

3 thoughts on “The Link Between Laron Syndrome And Increased Longevity And Cancer Decrease

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  2. TERRY KAUFMAN

    I am working on a short presentation on human longevity and have been reading about the Laron Syndrom. Can you tell me what the greatest age attained by a person with Laron Syndrom.

    1. TERRY KAUFMAN

      Can you tell me what the greatest age attained by a person with Laron Syndrom.

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