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. Last Updated: 07/27/2016

Long-Lived Villagers With a Lucky Gene

LIMONE, Italy -- On the edge of Lake Garda in northern Italy, this tiny fishing village attracts thousands of tourists from all over the world. Each summer, they invade in busloads to enjoy Limone's blue waters against the backdrop of the majestic Dolomite mountains.


But lately, Limone's tranquility has been stirred up by a new group of visitors: a team of scientists who are studying a small number of residents known here as the portatori, or the carriers.


The portatori go about their daily chores without paying too much attention to the scientists. But the inquisitive researchers are hard to ignore: the portatori have had more than their fair share of blood drawn by the scientists, who have been trying to unravel a medical mystery: Why are the portatori immune from heart disease?


Some speculated it was the olives or lemons growing on the hillsides that help the residents of Limone live to a ripe old age. Others thought it was their hikes up and down the mountainsides.


It turns out the portatori carry a unique protein in their blood that prevents them from developing heart disease. The protein, like a street cleaner removing debris, carries cholesterol out of their arteries at a much faster pace than in normal people.


"It is very interesting that nature has given us a model in human beings," says Dr P.K. Shah, one of the researchers examining the protein. "These individuals in Limone who carry this protein have a history of longevity. Most of them have lived into their eighties and nineties."


So far, the protein is found nowhere else other than in the portatori of Limone. The discovery could provide new hope in the treatment of strokes, arteriosclerosis and other heart disease caused by the buildup of fat in veins and arteries, which kills hundreds of thousands of people each year.


The protein has been the subject of research by scientists from the University of Milan to the National Institutes of Health in Bethesda, Maryland. In Los Angeles, scientists working with Shah at Cedars Sinai Medical Center have found a dramatic, 70 percent decrease in the amount of fat deposits, in the arteries of rabbits after they were given the protein.


Some of the most exciting work is taking place in Stockholm, Sweden, where researchers are in the process of developing a drug from the protein, which may offer the rest of mankind protection from heart disease.


"There are a lot of problems in developing a human drug, but at the moment what we see today is rather exciting," says Dr. Cesare Sirtori, the scientist at the University of Milan who studied the portatori in Limone and discovered their secret.


Scientists at the Swedish pharmaceutical company Pharmacia in Stockholm have reproduced the protein in their laboratories in large quantities, and it has proven remarkably effective in animal tests in Milan and Stockholm.


Of course, the portatori provide a living laboratory. Each of the 44 portatori carry a gene -- the result of a genetic mutation that occurred over two centuries ago -- that triggers production of the protein, named Apo A1 Milano by the Milan scientists who identified it.


The scientists have traced the genetic mutation back to a couple, Cristoforo Pomaroli and Rosa Giovanni, who wed in 1760. Their son, Giovanni, carried the protein-producing gene that mutated into the form that has passed through 10 generations to today's lucky carriers.


A stroll through the cemetery here reveals many of the original portatori who carried the gene and passed in on to their descendants, such as Cristoforo Pomaroli, Giuseppi Segala and Giovanni Dagnoli, who lived to be 86.


It was when Dagnoli's son, Valerio, a railroad worker in Milan, went to see a doctor 20 years ago that the mystery of the mutant gene began to unravel. Dagnoli had such high levels of bad cholesterol in his blood that a normal man would have been crippled with serious cardiovascular problems.


"For medical science and for all the doctors I was at death's door. But I was actually fine," recalls Dagnoli, now 62.


For some reason his heart and arteries were clear of fat deposits. So his doctor sent him to the University of Milan to see Sirtori, a pharmacologist who treats people with high cholesterol.


After tests made it clear that Dagnoli had inherited a unique gene, "I asked him, where do you come from," Sirtori recalls. "He said, I come from Limone." So Sirtori came to this village and tested the blood of each one of its 1,000 residents. Through the tests, he discovered 44 also had the protein -- all of them having common ancestors from whom they had inherited the gene.


Sirtori discovered that many of their ancestors had intermarried, most likely because Limone had been isolated from the rest of the world for centuries by the high mountains and huge lake.


"They intermarried for generations, so they had the chance of developing one good gene," Sirtori says. "What is unusual and unique is that when we talk about human mutations we always talk about disease. Instead, they developed a good gene."


Today the portatori go about their business all over the village. Rolando Tosi and his father run a souvenir store. Across the street his sister, Marcia, operates an ice cream parlor. Up the hill, Felicita Fava waters her flowers.


The portatori have a one in four chance of passing the gene on to their offspring. To improve those odds, Sirtori has offered a car to any couple who marry and who are both portatori. But nobody has taken him up on the offer yet.