Scientists at Northwestern University have discovered a genetic mutation in an isolated Amish population that helps them live longer and healthier lives, and protects them from diabetes and other age-related illnesses. A drug that mimics those effects is currently being trialled in humans, and shows promise in slowing aging, preventing diabetes and may even counteract baldness.

The mutation was discovered in an Amish extended family (or "kindred") living in Berne, Indiana, part of a community that has largely remained genetically isolated for over a century. Carriers were found to live on average 10 percent longer (about 14 years) than those without, be significantly less likely to develop diabetes and have much healthier vascular systems into old age. Their telomeres – protective caps on the ends of chromosomes that shorten with age – were 10 percent longer than average, and they had much lower fasting insulin levels.

"The findings astonished us because of the consistency of the anti-aging benefits across multiple body systems," says Douglas Vaughan, lead author of a paper describing the find. "For the first time we are seeing a molecular marker of aging (telomere length), a metabolic marker of aging (fasting insulin levels) and a cardiovascular marker of aging (blood pressure and blood vessel stiffness) all tracking in the same direction in that these individuals were generally protected from age-related changes. That played out in them having a longer lifespan. Not only do they live longer, they live healthier. It's a desirable form of longevity. It's their 'health span'."

A protein called plasminogen activator inhibitor (PAI-1) seems to be behind the benefits. PAI-1 has been linked to aging in other animal models, and Amish individuals with the mutation have far lower levels of the protein. Although less PAI-1 sounds like a good deal so far, too little can be a problem in itself, and it's these negative effects that first brought the mutation to the attention of scientists.

Certain members of this Old Order Amish community were found to have issues with severe bleeding after injuries. In the early 1990s a young girl almost died from excessive bleeding after bumping her head, and on examination she was found to have a rare bleeding disorder on account of a PAI-1 deficiency. Further tests on her immediate family found that the condition was genetic.

The girl and some of the other affected people were found to have two mutated copies of a particular gene, which causes an absence of PAI-1 in the blood, and since the protein plays a role in clotting, its absence leads to bleeding issues. But far more of the people tested only carried one copy of the mutated gene, and they were found to not have the same problem.

When the Northwestern scientists read over papers published in the 90s describing the mutation, they wanted to investigate the impact it would have on cardiovascular health and aging in general.

"That was the gateway that could allow us to investigate the impact of a partial PAI-1 deficiency over a lifetime," says Vaughan."The work in the lab and the science of aging kept pointing to a relationship between PAI-1 and aging itself. We had showed in a previous study in mice that a partial deficiency of PAI-1 protected against aging-like changes. Was that true for human beings, too? Now we had an incredible, unique opportunity to test our hypothesis."

To do so, the researchers set up a temporary facility in a community center and ran a series of tests on 177 Amish people from the community. This included echocardiograms, systolic blood pressure, pulse wave velocity and pulmonary function tests. Urine, blood and fibroblast samples were also taken from participants.

The ages of those tested ranged from 18 to 85, with the average being in the mid-40s. The study focused on those individuals that had just one mutant copy of the gene, and these people were found to have about half as much PAI-1 as a base group with two normal copies. That led to a number of apparent health benefits.

Since seven percent of the base group have diabetes, the researchers expected about three or four percent of those with the mutation to have the disease. But to their surprise, none of them did: they were completely protected from diabetes, boasting 30 percent lower fasting insulin levels. The affected people also had cardiovascular systems that appeared much "younger" than unaffected individuals, with reduced pulse pressure indicating more flexible arteries.

In partnership with a Japanese company called Renascience, the Northwestern researchers are currently developing drugs that inhibit PAI-1 in order to achieve some of these anti-aging benefits. In tests on mice engineered to overproduce PAI-1, a surprising side effect was discovered: the mice that had previously gone bald had started regrowing hair. Since then, developing a potential baldness treatment from the drug has become a side project.

Phase 1 human trials have recently been completed in Japan, where the drug was given to 160 people and proved to be safe and nontoxic. The researchers say that the drug should be safe as long as it only partially inhibits the protein – you don't want to end up with excessive bleeding, after all. Phase 2 trials are now underway, with a focus on whether reduced PAI-1 has an effect on how stem cells migrate out of bone marrow.

The research was published in the journal Science Advances.

Source: Northwestern University