An Amish toddler’s head wound in the early 1990s, which bled uncontrollably and nearly killed her, has led decades later to a promising new anti-aging therapy currently being tested in Japan, according to researchers at Northwestern University Feinberg School of Medicine.
The latest findings of a rare genetic mutation called SERPINE1 found in the DNA of the small community of Old Order Amish in Berne, Indiana is reported in the journal Science Advances this week.
The mutation was associated with longer lifespans, longer telomeres at the ends of chromosomes, better cardiovascular health, and the non-existence of diabetes, the researchers said this week.
“For the first time we are seeing a molecular marker of aging (telomere length), a metabolic markers of aging (fasting insulin levels) and a cardiovascular mark 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,” said Douglas Vaughan, a cardiologist and the lead author of the work. “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.’”
The study involved testing 177 Amish who voluntarily gave their blood and submitted to tests in May 2015, arriving at a local community center by horse and buggy, and on foot. The secluded group allowed some 40 doctors and other medical staff to take samples and run tests including echocardiograms, blood pressure readings, pulse wave velocity, pulmonary function evaluations, and urine samples.
The medical experts were looking for the genetic mutation – and the protein that it codes for, called plasminogen activator inhibitor, PAI-1.
The normally-reluctant group agreed to participate, Vaughan said, because of a health phenomenon throughout their community.
A toddler who had bumped her head at the age of three had nearly died of uncontrollable bleeding in the early 1990s. Doctors investigated her blood – and found a deficiency of PAI-1, the school explains in a release accompanying the new publication.
The girl’s DNA revealed that she had two copies of a mutated gene that led to a complete absence of PAI-1, which helps with clotting – but also showed a link to natural aging and pathology.
The scientists continued to look into the sheltered community, beyond the one little girl’s blood. The investigators found varying degrees of the gene among the 10,000 people who came to make up their investigational family tree. They found a dozen with the double-copy mutation that caused the bleeding disorder – but they also found dozens more who carried just a single copy of the gene.
Those people with the single gene showed better health, and longer lives – leading to the decades of research culminating in the current paper, they added.
“This is the only kindred on the planet that has this mutation,” said Vaughan. “It’s a ‘private mutation.’”
The new findings of the 177 Amish indicates that they have lower levels of PAI-1. Along with that mutation came 30 percent lower fasting insulin levels, and none had diabetes. Lower blood pressure, more flexible blood vessels, reduced pulse pressure, and younger cardiovascular systems all came with the advantage of the single gene, they add.
“In conclusion, our data indicate that PAI-1 is associated with a number of parameters that may reflected biological aging, including LTL, metabolism, and life span,” they write. “Overall, our findings are the first to identify the physiological association of a null mutation in PAI-1 with LTL and life span in humans and suggest that PAI-1, a component of the senescence-related secretome, may influence the aging process.”
Now a drug is in phase II clinical studies currently based on the concept of the PAI-1 findings. TM5614, an oral treatment, inhibits PAI-1, and is being investigated by doctors at Tohoku University. Northwestern and the drug start-up Renascience have proven its safety in 160 patients – and the viability tests are underway in Japan, while U.S. trials are expected to proceed in the next six months, they said.
Vaughan previously showed in a 2014 paper in the Proceedings of the National Academy of Sciences that the drug tripled the lifespans of rapidly-aging mice.