PAI-1 Mutation in Amish Community Could Lead to New Treatments for Age-Related Disorders

In the early 1990s, a paper was published in the New England Journal of Medicine that documented a unique and interesting case. An Amish girl, 9 years of age at the time, got a bump on her head. A normal enough childhood incident, but in this case the bleeding did not stop on its own and required surgery. While it was clear that she had some type of clotting disorder, her case didn’t seem to fit the usual pattern of known conditions; she didn’t have hemophilia, nor did her symptoms fit with other well-known blood disorders.

The doctors treating her took a blood sample and found an uncommon mutation in the girl’s SERPINE1 gene that was believed to result in PAI-1 deficiency, which could lead to problems clotting. Because the Amish community is relatively tight-knit, the doctor tested other individuals in the same town who exhibited the same bleeding condition and found that the symptomatic individuals all presented with a complete PAI-1 deficiency, meaning that all symptomatic individuals had a total lack of PAI-1 protein.

There were other interesting discoveries happening around this same time, including work demonstrating that PAI-1 could play a role in cardiovascular disease which lead to further developments suggesting that PAI-1 could be a component in cellular senescence as well. Cellular senescence occurs when a cell essentially “sleeps” and halts further cell division/replication, a phenomenon that plays a role in functions like slowing cancer development. Once the line from PAI-1 to senescence was drawn, the next step was to look at the impacts of senescence on aging and whether PAI-1 plays a role.

Mouse studies from the early 2000s, a little more than a decade after the New England Journal of Medicine article was published, were showing that lower levels of PAI-1 protected mice from rapid aging. Researchers wanted to know if similar results would be found in humans - where lower PAI-1 levels might lead to beneficial health outcomes as observed in mice - but without causing disease or disorders like the bleeding condition that can result from a complete deficiency.

The Amish community studied in the 90s provided a unique opportunity to learn more about this genetic mutation and how PAI-1 could play a role in more than just coagulation. The girl from the original study, now a grown woman, had inherited the SERPINE1 mutation from both parents which lead to a complete PAI-1 deficiency (and therefore a bleeding disorder). In direct contrast, family members who inherited only one copy of the SERPINE1 mutation had lower levels of PAI-1 (roughly half the typical amount seen in individuals without the mutation) but did not have a complete deficiency or a bleeding disorder.

Other genetic disorders that are inherited by having two copies of a genetic variant operate in a similar manner. Individuals who inherit the genetic variant from both parents suffer from the genetic disorder, while individuals with only one copy of the genetic variant do not inherit the disorder (but could pass the gene along to their offspring). Interestingly, in some of these genetic disorders the individuals who inherit a single copy of the genetic variant seem to have an advantage over individuals who don’t inherit the variant. For example, individuals who have a single copy of the defective gene that causes sickle-cell disease don’t present with the disorder but seem to survive malaria infection at an increased rate when compared to those without the defective gene.

This seems to be the case when it comes to the genetic mutation in SERPINE1 that causes PAI-1 deficiency, as well. While having two copies of this gene can result in bleeding disorders, having a single copy of this gene results in better health outcomes like a longer lifespan (10 years longer, on average), a lower risk of diabetes as compared to others in the same community, and a decreased incidence of heart disease.

While this isn’t quite the Fountain of Youth that Ponce de Leon famously traveled the world in search of, it does identify PAI-1 as a potential target for future therapeutic approaches. Because there is an existing population of individuals genetically expressing lower PAI-1 levels without harmful outcomes – and seeing better outcomes seemly as a result of the reduction in PAI-1 expression – it will likely be easier to develop treatments aimed at reducing PAI-1 levels as this reduction is potentially safe and could be beneficial.

Researchers are working on investigational therapeutics aimed at partially inhibiting PAI-1 such that benefits are seen while health problems are not. Early animal tests are promising, and researchers hope that this will help them to develop treatments for a wide range of conditions like chronic kidney disease (which can lead to an increased risk of heart disease), Alzheimer’s disease, diabetes, and fibrotic diseases like systemic sclerosis.

The goal of these types of treatments is not to create the proverbial Fountain of Youth, allowing people to live greatly extended lives, but rather to suppress common age-related diseases which would make it possible for people to remain healthier longer into their lifespan. Currently there are investigational drugs entering Phase I and Phase II of testing, the results of which will undoubtedly be exciting to see.

Resources and Further Reading:

• Fay, W. P., Shapiro, A. D., Shih, J. L., Schleef, R. R., & Ginsburg, D. (1992). Complete Deficiency of Plasminogen-Activator Inhibitor Type 1 Due to a Frame-Shift Mutation. New England Journal of Medicine, 327(24), 1729–1733.doi:10.1056/nejm199212103272406 
• Khan, S. S., Shah, S. J., Klyachko, E., Baldridge, A. S., Eren, M., Place, A. T., … Vaughan, D. E. (2017). A null mutation in SERPINE1 protects against biological aging in humans . Science Advances, 3(11), eaao1617.doi:10.1126/sciadv.aao1617 
• Gene Variant in Amish a Clue to Better Aging. Genetic Engineering & Biotechnology News: Feb 1, 2018 (Vol. 38, No. 3)