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Rare Mutation Found Among Amish Population Protects Against Some Effects of Aging

NEW YORK (GenomeWeb) – A rare loss-of-function mutation found among Old Order Amish individuals protects against some of the effects of aging, a new study has found.

The mutation, located in the SERPINE1 gene, affects the function of plasminogen activator inhibitor-1 (PAI-1), which has a role in cellular senescence and is expressed at higher levels in senescent cells, leading the researchers to suspect that variants in this gene could influence aging and cardiometabolic disease, which affect lifespan.

A team of Northwestern University researchers studied 177 members of the Berne Amish community, nearly a quarter of whom carried the SERPINE1 mutation. As the team reported today in Science Advances, heterozygous carriers of this mutation had longer telomeres, lower fasting insulin levels, and lower incidence of diabetes, all of which are related to aging. In addition, mutation carriers were longer-lived than other Amish individuals.

"Overall, our findings are the first to identify the physiological association of a null mutation in PAI-1 with [leukocyte telomere length] and lifespan in humans and suggest that PAI-1, a component of the senescence-related secretome, may influence the aging process," Northwestern's Douglas Vaughan and his colleagues wrote in their paper.

The researchers' cohort of 177 people included 43 individuals from the Berne Amish community who were carriers of the null SERPINE1 mutation and seven individuals who were homozygous for the mutation. Heterozygous individuals had lower circulating plasma PAI-1 levels, as compared to controls, while homozygous individuals had no discernable PAI-1 in their blood, which the researchers said was consistent with the variant being a loss-of-function mutation.

Overall, the researchers reported that the unaffected members of their Amish cohort had lower body-mass index, fasting glucose, and triglyceride levels than individuals from the Coronary Artery Risk Development in Young Adults Study cohort. This suggested that their Amish cohort might be, in general, healthier than the wider US population.

Participants' mean telomere lengths, as gauged from their leukocytes, correlated with age, becoming about 9 percent shorter with each decade, among the unaffected participants. SERPINE1 mutation carriers, however, had telomeres that were an average 10 percent longer.

The researchers also had vital statistics for 221 people. From that data, they found that people with SERPINE1 mutations tended to live longer than those without — 85 years versus 75 years, respectively.

Similarly, the researchers investigated whether SERPINE1 mutation status affected the prevalence of aging-related conditions like diabetes. They found that individuals with the SERPINE1 mutation had lower BMIs, lower prevalence of diabetes, and lower fasting insulin levels than those with wild-type SERPINE1.

The researchers also noted that there is a high degree of relatedness among their Amish cohort. They traced the null SERPINE1 mutation within this population back to a husband-and-wife common ancestor that lived about six generations ago. Because of this relatedness, the researchers said that other inherited genetic or epigenetic factors could also influence aging in these individuals.

The researchers acknowledged that their results might not be generalizable as their Amish cohort is generally healthier than the wider population and the mutation under study is a rare, private mutation. Still, they said that PAI-1 appears to be involved in aspects of biological aging.

"Future studies will provide the opportunity to investigate the contribution of PAI-1 to individual telomere attrition over time, the development of incident diabetes and other age-related diseases, and perhaps ultimately differences in health and life span in humans," the authors wrote.