A particular mutation identified among Old Order Amish in Indiana is associated with a longer life span, improved metabolism and a lower occurrence of diabetes, according to a new study. The findings demonstrate the utility of studying mutations in populations with geographic and genetic isolation, and shed light on a novel therapeutic target for aging. Aging remains one of the most challenging biologic processes for scientists to unravel, due in part to the many interrelated molecular and cellular changes it brings. One indicator of aging is the shortening of telomeres, caps at the end of strands of DNA that protect a person's chromosomes. Progressive shortening of telomeres leads to senescence, or biological aging. Senescent cells and tissues exhibit a distinctive pattern of protein expression, including increased production of plasminogen activator inhibitor-1 (PAI-1). To further examine the role of PAI-1 in human longevity, Sadiya Khan and colleagues studied 177 members of the Berne Amish community. Forty-three of these men and women carried a nonfunctional copy of the gene SERPINE1, which encodes PAI-1. Carriers of this SERPINE1 mutation lived an average of 10 years longer than other individuals in the community. What's more, they had a 10% longer average white blood cell telomere length, after adjusting for age, sex, and familial relatedness compared with noncarriers. The authors say future studies will be needed to investigate the contribution of PAI-1 to individual telomere shortening over time, the development of incident diabetes, and other age-related diseases, and perhaps ultimately differences in health and lifespan in humans.