Rare genetic mutation found in Amish community could combat ageing

Amish boys watch a game of baseball. In the population studied, those with the mutation were found to have better metabolic health, far less diabetes, and tended to live a decade longer than others without the mutation.

In the Amish population studied, those with the mutation were found to have better metabolic health, far less diabetes, and tended to live a decade longer than others without the mutation.

The discovery of a rare genetic mutation that prolongs human life has raised hopes for new treatments to combat ageing and prevent age-related disorders from heart disease to dementia.

Researchers spotted the mutation in an Amish population in Indiana where carriers were found to have better metabolic health, far less diabetes, and tended to live a decade longer than others in the community.

Scientists studied 177 members of the Old Order Amish in the town of Berne and identified 43 people who had inherited one normal and one mutated version of a gene called Serpine1. Those with the mutated version of the gene typically lived to 85 years old, a full 10 years longer than those who did not carry the mutated form.

“This is a rare genetic mutation that appears to protect against biological ageing in humans,” said Douglas Vaughan, a professor of medicine who led the research at Northwestern University in Chicago.

The Serpine1 gene provides the body with instructions to make a protein called PAI-1 which serves as a brake on a process that destroys any clots that may build up in blood vessels. But the protein also has a hand in a process called senescence, where cells go into a state of suspended animation and steadily build up in the body’s tissues. Senescence is increasingly thought to be a strong driver of the ageing process.

Studies in animals have shown that reducing levels of PAI-1 can protect them against ageing and age-related diseases and even prolong life, but until now, the same effect had not been seen in humans. The Amish group in Indiana are the only known community to carry the mutation that naturally suppresses levels of PAI-1 in the blood.

Writing in the journal Science Advances, the researchers describe how those with the single mutated gene had 50% lower levels of PAI-1 in their blood. The scientists went on to look at biological markers for ageing, known as telomeres, in the individuals. Telomeres are tiny caps that tip the ends of chromosomes and which get shorter with age. Carriers of the mutation had longer telomeres than others, suggesting they had aged more slowly, the scientists report.

Tests found a range of health benefits in those who carried the mutation, including better metabolic health, lower levels of diabetes, and a longer lifespan.

A small number of people in the community were found to have two mutated copies of the gene, and no detectable PAI-1, but this often led to a bleeding disorder, the scientists found. The oldest affected person is only about 30 years old, so researchers cannot yet tell what impact the double mutation might have on lifespan. “It seems that there’s a sweet spot. You don’t want too much PAI-1, and you don’t want zero,” said Vaughan.

Trials are already underway into drugs that can slightly reduce blood levels of PAI-1. The diabetes drug, metformin, does this to some extent, but researchers at Tohoku University in Japan have begun human trials of a new drug that directly targets PAI-1.

If the trials are successful, the drug could potentially be used to delay the onset of age-related diseases, and treat some patients with conditions that cause them to age prematurely. “We are very optimistic about its potential role not just in slowing ageing but in reducing age-related morbidities,” Vaughan said.

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