CreditCourtesy of Indiana Hemophilia & Thrombosis Center
Amish people living in a rural part of Indiana have a rare genetic mutation that protects them from Type 2 diabetes and appears to significantly extend their life spans, according to a new study.
The findings, published on Wednesday in the journal Science Advances, shed light on the processes underlying cellular aging and could lead to new therapies for chronic diseases, some experts say. The researchers are planning at least one follow-up trial that will recreate the effects of the mutation so they can study its impact on obese people with insulin resistance, a precursor to diabetes.
The mutation described in the new paper affects a mysterious protein called plasminogen activator inhibitor-1, or PAI-1, that is known primarily for its role in promoting blood clotting. The mutation was first identified in 1991 in a secluded Amish farming community in Berne, Ind. An estimated 5 percent of the community carries the mutation, which causes them to produce unusually low levels of PAI-1.
Scientists have long suspected that PAI-1 has other functions outside of clotting that relate to aging. Dr. Douglas Vaughan, a cardiologist at Northwestern medical school, noticed, for example, that mice that had been genetically engineered to produce high levels of the protein age fairly quickly, going bald and dying of heart attacks at young ages. People who have higher levels of the protein in their bloodstreams also tend to have higher rates of diabetes and other metabolic problems and to die earlier of cardiovascular disease.
Dr. Vaughan wondered how the Amish people in Berne who naturally produce smaller amounts of PAI-1 are affected. So two years ago he reached out to the community and asked if he could study them.
When they agreed, Dr. Vaughan took a team of 40 researchers to their town, set up testing stations in a recreation center, and spent two days doing extensive tests on 177 members of the community, many of whom arrived by horse and buggy. The researchers pored over birth and death records and took extensive genealogical histories. They drew blood, did ultrasounds of their hearts, and rigorously examined their cardiac and pulmonary function.
Some of the young men we collected blood from fainted because they had never had a needle stick in their life, said Dr. Vaughan, who is chairman of medicine at the Northwestern University Feinberg School of Medicine. These people live sort of an 18th century lifestyle and generally dont take advantage of modern medicine. But they were so gracious and courteous and cooperative.
What Dr. Vaughan and his colleagues discovered was striking. Amish carriers of the mutation live on average to age 85, about 10 years longer than their peers. Among the Amish who did not have the mutation, the rate of Type 2 diabetes was 7 percent. But for carriers of the mutation, the rate was zero, despite leading the same lifestyle and consuming similar diets. Tests showed that carriers of the mutation had 28 percent lower levels of insulin, a hormone whose chronic elevation can lead to Type 2 diabetes.
Diabetes is something that develops more as we age, Dr. Vaughan said. This is a terrific indicator that the mutation actually protected them from a metabolic consequence of aging.
The carriers also appeared to be in better cardiovascular health, and they had 10 percent longer telomeres, the protective caps at the ends of chromosomes that are akin to the tips of shoelaces. Telomere length is seen as a barometer of biological aging, with longer telomeres linked to longevity.
Jan M. van Deursen, a molecular biologist and expert on aging at the Mayo Clinic, who was not involved in the new research, said the study was impressive and yielded intriguing insights.
I think its nice work, you dont see these types of studies that often, he said. The Amish are quite reserved, and its not that easy to get them to participate in a study like this. My hats off to them and to the researchers.
Although the exact mechanism is unclear, Dr. Vaughan and his colleagues believe that PAI-1 somehow helps accelerate the aging process. It could be that PAI-1 promotes insulin resistance and impairs glucose metabolism. Or the protein could work through senescent cells, which accumulate in aging tissues and cause inflammation. PAI-1 is one of the inflammatory agents that senescent cells typically secrete, and its possible that the Amish mutation disrupts that process.
The Indiana community has been involved in other research, includinga study last year that foundthat exposure to barnyard dust helps to protect children against asthma. Dr. Vaughan and his colleagues, including Dr. Amy Shapiro, a hematologist who first discovered the mutation, are hoping to do more studies with the Amish to see how the PAI-1 mutation affects cognitive function and other aspects of health.
A team at Tohoku University in Japan led by Dr. Toshio Miyata has developed a drug that inhibits PAI-1 and that, in an early trial, appears to be safe. Dr. Vaughan plans to seek permission from the Food and Drug Administration to start a trial in the United States as early as next year to examine the effects of using the drug to lower PAI-1 in people who are obese or insulin resistant.
The researchers say their goal is not to inhibit PAI-1 completely, because of the proteins essential role in clotting.
Amish men and women who inherit two copies of the PAI mutation, one from each parent, for example, produce no PAI-1 at all and develop a bleeding disorder similar to hemophilia. So-called carriers who inherit just one copy of the mutation, however, produce less PAI-1 than the average person but still have enough of it to avoid any obvious clotting disorders or other downsides.
We know that a complete deficiency state is not a good thing, said Dr. Shapiro, the co-medical director of the Indiana Hemophilia & Thrombosis Center. But weve shown that there is an advantage to having low levels like the way the carriers do.
An earlier version of this article misstated that insulin levels are chronically elevated in diabetes. They are chronically elevated in prediabetes, which can lead to full-blown Type 2 diabetes.
Original Date: November 15, 2017
Original Author: Anahad O’Connor