The secret to longer life may be found in the Amish after scientists discovered older members of the traditional Christian community carry a gene which helps them live an extra 10 years.
A girl, who lived in an Indiana Amish community, nearly bled to death during what should have been routine scalp surgery. Now, more than 20 years later, scientists studying her and other Amish have discovered that the mutation that nearly killed her could have a good side. She harbors two mutant copies of a gene, and therefore lacks a protein that manages blood clotting, but researchers found that people with one inactivated gene copy outlive their peers by a decade and gain protection against diabetes.
“I think it’s a remarkable study,” says cardiologist William Fay of the University of Missouri in Columbia, who was part of the research team that originally identified the girl’s genetic defect but isn’t connected to the new work. The results provide “an important piece of evidence” about the role of the gene in aging. Moreover, researchers have already developed a potential therapy that targets the gene’s protein. A team in Japan is testing it in people who are at high risk of diabetic kidney disease, and researchers hope to launch clinical trials in the United States for conditions such as obesity.
Some Amish contain genetic mutations where there telomeres are longer, better protecting DNA
Cardiologist Douglas Vaughan of the Northwestern University Feinberg School of Medicine in Chicago, Illinois, who led work published this week in Science Advances, tracked down the original patient because he and his colleagues suspected that the gene had roles beyond blood clotting. “I said, ‘I’ve been thinking about you for a long time,’” he recalls. “She looked at me like I was some sort of weirdo.” Nevertheless, she and 176 other members of her community agreed to take part in a study.
Researchers had already unearthed evidence that plasminogen activator inhibitor type 1 (PAI-1), the protein encoded by the gene, influences aging-related illnesses. PAI-1 levels shoot up in people who are obese or have type 2 diabetes or cardiovascular disease, for instance. Mice that make extra of the protein show signs of premature aging. PAI-1 may help drive cellular senescence, a potential key contributor to aging in which cells lose the ability to divide.
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The Amish group in Indiana offered a unique opportunity to probe further. Hundreds of its members, descended from a couple who emigrated from Switzerland six generations ago, carry “knockout” mutations of the gene, called SERPINE1. Like the girl, a few of them have two mutated copies, but most have one faulty and one normal copy. The researchers ran physiological tests on 43 people with one mutated gene and compared them with others in the community with two normal versions.
Individuals with one altered gene had longer telomeres, the caps on the ends of chromosomes that wear away as we get older, and appeared to be protected against diabetes, the researchers report. The genetic glitch also correlated with lower insulin levels, a sign of better metabolic health.
Using death records and family histories, the team determined that the median lifespan for people with one copy of the mutation was 85 years—10 years longer than for other community members. “There’s a potential protective effect here,” says human geneticist Andrew Johnson of the National Heart, Lung, and Blood Institute in Framingham, Massachusetts.
More evidence may come from clinical trials of a molecule that blocks PAI-1, developed by Vaughan’s colleagues in Japan. Besides treating diabetic kidney disease, Vaughan believes it could also benefit people with obesity and an age-related metabolic condition—“an exciting possibility,” Johnson says.
But would this strategy be safe, given the protein’s importance for blood clotting? Fay notes that people who harbor one mutated copy of the gene seem to have normal blood clotting, so blocking PAI-1 might not trigger dangerous bleeding. But Johnson says he’s unsure whether researchers can “get the right amount of inhibition” to produce a health benefit without triggering serious side effects.
Scientists say the finding sheds light on aging, and hints at a way to extend life through targeting the protein or gene with drugs.
Source: doi:10.1126/science.aar4945