A common genetic mutation is linked to an increase in life span of about 20 years among men, researchers reported on Friday.
The mutation, described in the journal Science Advances, did not seem to have any effect on women. Still, it joins a short list of gene variants shown to influence human longevity.
By studying these genes, scientists may be able to design drugs to mimic their effects and slow aging. But the search for them has been slow and hard.
When it comes to how long we live, nurture holds powerful sway over nature. In 1875, for example, life expectancy in Germany was less than 39 years; today it is over 80.
Germans didn’t gain those extra decades because of evolving, life-extending changes in their genes. Instead, they gained access to clean water, modern medicine and other life-protecting measures.
Nevertheless, heredity clearly plays a modest role in how long people live. For example, a number of studies have shown that identical twins, who share the same genes, tend to have more similar life spans than fraternal twins.
In a 2001 study of Amish farmers in Pennsylvania, researchers found that close relatives were more likely to live to similar ages than distant ones.
The impact of heredity on life span has turned out to be about as big as its influence on developing high blood pressure. But large-scale surveys of people’s DNA have revealed few genes with a clear influence on longevity.
“It’s been a real disappointment,” said Nir Barzilai, a geneticist at Albert Einstein College of Medicine.
Researchers are having better luck following clues from basic biology. In many species, for example, there is a relationship between an animal’s size and its life span.
“If you look at dogs, flies, mice, whatever it is, smaller lives longer,” said Gil Atzmon, a geneticist at the University of Haifa in Israel who collaborates with Dr. Barzilai.
Results like these have led researchers to look closely at the molecules that cause our bodies to grow. One of the most important is growth hormone, which is produced in the brain and courses through the body.
The hormone latches on to cells, binding to a surface molecule called a growth hormone receptor. This signal can trigger cells to grow faster. The cells may also release signaling molecules of their own, known as growth factors.
About a quarter of people have a mutation in the gene for growth hormone receptors — a chunk of DNA is missing.
People with this mutation can make working receptors, but their shape is slightly different. Studies in the mid-2000s suggested that this mutation might make children short.
The link between height and longevity led Dr. Atzmon and his colleagues to wonder if it might also influence how long people lived.
The researchers sequenced the gene for growth hormone receptors in 567 Ashkenazi Jews over 60 and their children, whom Dr. Barzilai had been studying for years.
The mutation, they found, was present in 12 percent of the men over age 100. That rate was about three times higher than in 70-year-old men.
In women, however, the mutation was present in roughly the same fraction in both age groups.
Dr. Atzmon and his colleagues followed up by examining the gene in a group of long-lived people in the United States, another in France and a third in the Amish community, raising the total number of subjects to 814.
In all three groups, the researchers observed the same effect. Among men, the mutation in the gene for growth hormone receptors was linked to substantially longer lives.
“The results look convincing to me,” said Ali Torkamani, the director of genome informatics at the Scripps Translational Science Institute in La Jolla, Calif.
Dr. Torkamani, who was not involved in the new study, said it was the first to establish a link between growth hormone receptors and longevity.
“I definitely think there’s some fire there,” said P. Eline Slagboom, a geneticist at Leiden University Medical Center in the Netherlands.
But she had some reservations about the results, given that only men showed an effect and that the study was relatively small.
“It’s calling out for larger studies,” she said.
In 2008, Dr. Barzilai and his colleagues discovered that a mutation in another growth-related gene could extend life — this time, only in women. Combined with the new study, this research suggests that men and women take different genetic paths toward living long lives.
But the researchers don’t know what those paths might be. “This whole issue has shocked us,” Dr. Barzilai said.
The new study also shows that the link between life span and height is more complex than the scientists had anticipated.
They had expected that long-lived men with the mutation would be short. However, just the opposite turned out to be true: The mutation seemed to raise men’s height by about an inch.
Dr. Barzilai and his colleagues suspect that the mutation triggers a cascade of changes in the growth-spurring signals in men’s bodies, leaving cells less sensitive to low levels of growth hormone.
When growth hormone levels surge, however, these cells divide faster than those in men without the mutation. Somehow, the receptor amplifies the signal’s growth.
That sensitivity may spur the growth of boys during adolescence, when their bodies are flooded with growth hormone. But as the amount of hormone drops in manhood, their cells may divide more slowly, and they may stop producing growth-spurring molecules of their own.
Numerous studies suggest that extra growth signals can speed up aging. One theory is that there may be a trade-off in the body between growth and repairing molecular damage in cells.
Men with a mutation in their growth hormone receptor may put more resources into repairing their bodies, thus slowing the aging process.
In recent years, some doctors have prescribed growth hormone to patients to restore youth and give them strength. Dr. Barzilai said the new study suggests that keeping growth hormone levels low may actually be a better strategy for living longer.
“We’re worried about giving treatments that probably are going to do the opposite,” he said.
Dr. Barzilai and his colleagues now hope to mimic the effect of the newly discovered mutation by reducing growth hormone levels in older people.
Already they have produced some promising results in animal studies using a diabetes drug called metformin.
“It’s not far from reality,” Dr. Barzilai said.