Plasminogen activator inhibitor-1 (PAI-1) has been shown to be a key component 
of the senescence-related secretome and a direct mediator of cellular 
senescence. In murine models of accelerated aging, genetic deficiency and 
targeted inhibition of PAI-1 protect against aging-like pathology and prolong 
life span. However, the role of PAI-1 in human longevity remains unclear. We 
hypothesized that a rare loss-of-function mutation in SERPINE1 (c.699_700dupTA), 
which encodes PAI-1, could play a role in longevity and metabolism in humans. We 
studied 177 members of the Berne Amish community, which included 43 carriers of 
the null SERPINE1 mutation. Heterozygosity was associated with significantly 
longer leukocyte telomere length, lower fasting insulin levels, and lower 
prevalence of diabetes mellitus. In the extended Amish kindred, carriers of the 
null SERPINE1 allele had a longer life span. Our study indicates a causal effect 
of PAI-1 on human longevity, which may be mediated by alterations in metabolism. 
Our findings demonstrate the utility of studying loss-of-function mutations in 
populations with geographic and genetic isolation and shed light on a novel 
therapeutic target for aging.