A mutation that can extend the human life span has been identified in the Amish community, after first having been detected in mice. The genetic change is also associated with improved metabolism and lowering the likelihood of chronic diabetes, scientists reported Wednesday in the journal Science Advances. Theoretically, the gene could be a therapeutic target for aging, they suggest.
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The human study, conducted by Sadiya Khan of Northwestern University and her colleagues, followed the observation that inhibiting a protein called PAI-1 in mice prolonged their little lives. In short, PAI-1 turns out to play a critical role in regulation of aging in both mouse and man.
PAI-1 is produced chiefly by the cells of our blood vessels. It stands for plasminogen activator inhibitor–1. We need PAI-1 in order for our blood to clot. Have too much PAI-1 and you risk inconvenient blood clots and arterial plaque (atherosclerosis). Have too little and you risk mild bleeding to hemorrhage.
Carriers of the mutated version of Serpine1, the gene that codes for PAI-1, suffer from intensified bleeding upon injury.
A high incidence of utter PAI-1 deficiency had previously been discovered among the Old Order Amish population of eastern and southern Indiana, originating in a pathogenic founder variant. In other words, PAI-1 deficiency in the community stemmed from a single person who had the mutation generations ago, but lived long enough to procreate.
Old Order Amish are a relatively conservative group in the Amish community. Among other practices, they eschew modern conveniences such as cars, and forgo churches in favor of meetings in the home. They also advocate having large families, strictly with fellow members of the church. Their closed-knit community has existed since the 17th century.
Having realized that the Serpine1 mutation has an impact on the life span of mice, the team checked the state of the gene in 177 members of the Amish community in Berne, Indiana, 43 of whom proved to have the mutation. Carriers of this mutation lived an average of 10 years longer than other people in the community, the researchers wrote.
They also had lower fasting insulin levels, and lower prevalence of chronic diabetes.
Humans and other sexual creatures in general have two copies of each gene, one from the mother and one from the father. For what it’s worth, heterozygotes showed the effect of the PAI-1 mutation, meaning they didn’t need to inherit more than one copy of the gene from their parents.
“Our study indicates a causal effect of PAI-1 on human longevity, which may be mediated by alterations in metabolism,” the scientists explain. How it has this causal effect remains to be elucidated, but meanwhile, they say, the findings may well shed light on a novel therapeutic target for aging.