The first genetic
mutation in humans that protects from multiple aspects of aging has been
discovered in an extended family of Old Order Amish living in Berne, Indiana,
reports a research team at Northwestern Medicine.
- Rare genetic mutation in extended
Amish family protects them from effects of aging and increases longevity.
- It is the first genetic mutation
identified that protects human carriers from several aspects of aging.
- Amish who carry the mutation live
13% longer than their counterparts who do not carry the mutation.
- Mutation has allowed the synthesis of
a "longevity drug" for humans as well as a drug to fight baldness.
Amish individuals who carry the mutation live 10 percent longer than
their kindred who do not carry the mutation, says study. An experimental
"longevity drug" that simulates the effect of the anti-aging mutation is also
ready to be tested in human subjects to determine its protective effect on
The study findings are published in the journal Science
What does the mutation do?
Amish individuals who
carried the mutation had low levels of plasminogen activator inhibitor (PAI-1),
which is a protein that plays a critical role in cell aging and death.
While previous studies have shown that PAI-1 is related to aging in
animals, its effect on humans was unclear, until now.
Carriers of the mutation
who had a single mutated copy had lower fasting insulin levels that offer
protection from diabetes. They also
had lower blood pressure and more flexible blood vessels representing a younger
appearing cardiovascular system.
‘Amish who carry a rare mutation live 10 percent longer and have 10 percent longer telomeres than their kindred who do not carry the mutation.’
findings astonished us because of the consistency of the anti-aging benefits
across multiple body systems," said Dr. Douglas Vaughan, the lead author
of the paper who has been studying PAI-1 for almost 30 years.
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
and blood vessel stiffness) all tracking in the same
direction in that these individuals were generally protected from age-related
changes," Vaughan said. "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.'"
How was the mutation identified?
It was Dr. Amy
Shapiro, a hematologist at the Indiana Hemophilia & Thrombosis Center, who
decided to help the family of a nine year old toddler who had bumped her head when
she was three and had severe bleeding that required surgery. The girl almost
died from severe bleeding during the surgery and required blood transfusion.
She was the first old order Amish member identified with an unusual bleeding
disorder was identified to be the result of a genetic mutation that
led to deficiency of PAI-1.
Individuals who were affected with the rare
disorder had two copies of the mutant genes. Individuals with a single copy of
the gene were not affected
This was what
Vaughan had to say about Shapiro's study published in the New England
Journal of Medicine
the gateway that could allow us to investigate the impact of a partial PAI-1
deficiency over a lifetime," Vaughan said.
in the lab and the science of aging kept pointing to a relationship between PAI-1
and aging itself," Vaughan said. "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."
This led to
the hypothesis that giving people a drug that blocks PAI-1 partially might
provide protection against ill effects of aging as long as it provides
in partnership with Tohoku University in Japan are involved in the development
and testing of an oral drug, TM5614, which inhibits PAI-1.
The phase 1
clinical trials have been completed and the drug is now undergoing the phase 2
clinical trial in Japan.
An isolated population with an isolated mutation
population of Berne, Indiana, have been genetically and culturally isolated.
Most of them are also distantly related. Their ancestors were from Switzerland
who emigrated to Indiana in the middle of the 19th century. The Amish not
residing in Berne do not carry the anti-aging mutation.
the only kindred on the planet that has this mutation," Vaughan said.
"It's a 'private mutation.'"
A treatment for baldness
A new class of
drugs that specifically target PAI-1 was used to treat Vaughan's mouse model
that over expresses human PAI-1. The mice were bald, had heart attacks and
other pathologies caused due to excess of PAI-1. When the drug was fed to the
mice for six weeks, something unexpected happened. The mice started growing
hair! The research team is working toward the development of a formulation that
will be tested to treat male pattern baldness.
- Sadiya S. Khan, Sanjiv J. Shah, Ekaterina Klyachko, Abigail S. Baldridge, Mesut Eren, Aaron T. Place, Abraham Aviv, Eli Puterman, Donald M. Lloyd-Jones, Meadow Heiman, Toshio Miyata, Sweta Gupta, Amy D. Shapiro and Douglas E. Vaughan. A null mutation in SERPINE1 protects against biological aging in humans. Science Advances, 15 Nov 2017 DOI: 10.1126/sciadv.aao1617