If Peter Thiel wants to live forever, he might be better served sucking up the blood of the Amish instead of young people. A new study published in Science Advances illustrates how a particular gene mutation in an Amish community has conferred much of the population with a longer life span, better metabolism, and lower rates of diabetes. The findings could be a boon to understanding longevity in human beings and developing methods for increasing lifespan in future generations.
“It is a remarkable natural experiment,” Dr. Douglas Vaughan, a cardiologist based at Northwestern University’s School of Medicine and a coauthor of the study, said. “It gives us a glimpse into new approaches to reduce aging-related illnesses and perhaps extend the healthy lifespan of humans.”
At its core, the study hinges around proxy measures of telomeres, the capping ends of DNA strands which are meant to protect chromosomes from deterioration or from fusing with another chromosome. As DNA replicates, the telomeres shorten little by little, which creates what scientists call senescence (biological aging). As senescence increases, the body’s cells will increase the production of certain proteins more than others — and these proteins can be measured in order to assess aging in the body.
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One of the use proteins is plasminogen activator inhibitor-1, or PAI-1. But the role of PAI-1 in human longevity has never been fully understood. Vaughan and his colleagues from around the world decided to unravel this mystery.
The team enlisted 177 members of the Berne Amish community in Indiana and ran genetic analyses of each individual’s copy of SERPINE1, the gene that encodes for PAI-1. The team found 43 men and women exhibited a nonfunctional copy of SERPINE1, and that these carriers lived an average of 10 years longer than others in the same community.
“This-loss-of-function mutation in SERPINE1 effectively lowers the production of the protein PAI-1 by 50 percent in the individuals that carry one copy of the mutation,” says Vaughan. “This likely has multifactorial effects that reduce the internal signals and factors that drive senescence in cells and tissues, which in turn slows the aging process.”
None of the participants who possessed the mutated SERPINE1 gene exhibited signs of diabetes, but 7 percent with the normal SERPINE1 did. Moreover, the mutated SERPINE1 gene also correlated with lower-than-average levels of fasting insulin, which results in a heightened ability to metabolize food and nutrients.
Amish communities are famously tight-knit, and unique genes can become widespread through the population within just a few generations. According to Vaughan, the SERPINE1 mutation has been passed won’t through at least seven generations. The average lifespan of the Berne community, according to the results, is about 75 years — while those with SERPINE1 live to a median age of 85.
The mutation is incredibly rare in the general population, but there could be some ways to use the findings to develop practical interventions that could promote longer lifespans and healthier lives. “We certainly want to revisit the kindred and do additional testing to understand the effects on the velocity of aging and other aging-related changes,” he says. “The fact that Amish with a lifelong deficiency of PAI-1 suffer no apparent negative effects from this suggests that targeting the protein with a drug could be safely accomplished.”
Such a drug might be much closer on the horizon than we think. Early phase clinical trials with an orally active PAI-1 blocker are now underway by a team led by Dr. Toshio Miyata from Tohoku University in Japan. A biotech company called Renascience (based in Tokyo) holds the patent on the drug, and they’ve licensed a formulation of it to an American company called Eirion Therapeutics, who are moving forward to develop a topical preparation for the prevention and treatment of baldness. “It turns out one the ways PAI-1 contributes to aging is by limiting the mobilization and migration of cells, and this may be important in hair growth or the lack thereof,” says Vaughan.
The treatment of baldness isn’t quite the fountain-of-youth most of us are hoping for, but if that drug is proven successful and safe, it could be the first step towards manufacturing a PAI-1-blocking drug which actually does limit senescence in cells and creates tissues and organs in the body which are able to last longer and withstand the ravages of disease and old age. Although researchers are more concerned with how this could be used to treat specific illnesses which are exacerbated over time, a drug that targets PAI-1 or others like it could be one step towards longer lifespans. Who would have thought the Amish had the answer all along?
