Genetic studies of the Berne Amish of Indiana may shed light on aging and metabolic disorders such as diabetes. | Northeast Indiana Regional Partnership/ CC BY-NC 2.0
Residents of an Amish community in northeastern Indiana who had a nonfunctional copy of the gene SERPINE1 lived an average of 10 years longer than other individuals in the largely secluded community, researchers report in the November 15 issue of Science Advances.
Carriers of the mutation also had, on average, 10% longer white blood cell telomeres — the caps at the end of strands of DNA that protect a person's chromosomes — after adjusting for age, sex and familial relatedness compared with noncarriers. About a fourth of study participants carried the mutation, which is extremely rare in the general U.S. population.
The findings demonstrate the usefulness of studying mutations in populations with geographic and genetic isolation and shed light on a novel therapeutic target for aging, the researchers said.
"The Berne Amish community offers an unprecedented opportunity to examine how one rare genetic mutation in a gene connected with senescence and aging affected human health and life span," said Dr. Sadiya Khan, assistant professor of medicine at Northwestern University Feinberg School of Medicine.
This particular SERPINE1 mutation is specific to the study participants and stemmed from a shared ancestor, Khan said. Other rare nonfunctional or loss-of-function mutations in SERPINE1 have been reported at a frequency of about one in a million among individuals but are not prevalent in families, she said.
Aging remains one of the most complicated biological processes for scientists to disentangle and the findings are expected to contribute to the study of aging.
"One of the greatest challenges in unraveling how and why aging occurs are the complex interactions at every level within individuals," said Khan, the study's lead author.
Large-scale studies in humans have generally been disappointing in identifying specific factors that contribute to healthy aging and longevity, said Dr. Douglas Vaughan, a professor of medicine and chair of the Department of Medicine at Northwestern University Feinberg School of Medicine.
One aging indicator is the progressive shortening of telomeres, which leads to senescence, or biological aging. Senescent cells and tissues exhibit a distinctive pattern of protein expression, including increased production of the protein encoded by the SERPINE1 gene, known as the plasminogen activator inhibitor-1 (PAI-1).
The inhibitor regulates the breakdown of blood clots. Work over the past decade has also identified a broader relevance for the protein in the aging process, Khan explained.
To examine the role of PAI-1 in human longevity, Khan and colleagues studied 177 members of the Berne Amish community. Forty-three of these men and women carried a nonfunctional copy of SERPINE1.
Individuals with the SERPINE1 mutation had markers of delayed aging, no evidence of diabetes and longer life spans, Khan said. She was most surprised to find a lack of diabetes in individuals with the mutation, as diabetes is common in the general U.S. population.
Khan said the study participants were engaged and interested in understanding the science and potential to help others with this knowledge.
"In general, they were curious, although they don't spend a lot of time worrying about health care or utilizing modern health care services," Vaughan said. "Some had never had blood drawn before meeting us."
While the nonfunctional SERPINE1 mutation is extremely rare in the general population, understanding the role of PAI-1 is relevant, Khan noted.
"Interestingly, the most important predictor of PAI-1 blood levels in the general population is body mass index," Vaughan said, explaining lower PAI-1 levels are associated with a lower body mass index. "So, with the epidemic of obesity and diabetes we are witnessing now, it is certainly possible that PAI-1 is driving some of the complications — cardiovascular disease, for example — that we are seeing."
The researchers hope to return to the Berne community to continue their investigation. Future studies may further investigate the contribution of PAI-1 to individual telomere shortening over time, the development of new cases of diabetes and other age-related diseases and perhaps ultimately differences in health and life span in humans.
Vaughan said they also hope to start early phase clinical trials of a drug targeting PAI-1 in the near future.
"It is possible to imagine treating someone for a long time with a PAI-1 inhibitory drug," said Vaughan. "There are people over the age of 80 that have lived a lifetime with partial deficiency and do not suffer any untoward consequences. In fact, they appear to be healthier and live longer than their unaffected kindred."