Abstract 17320: Association of Loss-of-Function Mutation in SERPINE1 and Aging in Humans

Background: Plasminogen activator inhibitor-1 (PAI-1) is a key component of the senescence-related secretome and contributes to cellular senescence. Genetic deficiency and targeted inhibition of PAI-1 prolongs lifespan in an accelerated aging murine model. Identification of a unique Amish kindred from Berne, Indiana, a founder population that harbors a loss-of-function mutation in the PAI-1 gene, SERPINE1 (c.699_700dupTA), provides a novel opportunity to assess the effects of lifelong PAI-1 deficiency on aging in humans. Methods: To test the hypothesis that a loss-of-function mutation in SERPINE1 protects against biological aging, we enrolled and studied 177 members of the Berne Amish community. All participants were genotyped for SERPINE1. We tested the association of SERPINE1 status with molecular and physiological measures of aging after adjustment for age, sex, and relatedness in SOLAR. Results: Forty-three participants were heterozygous for the null SERPINE1 mutation with 50% lower plasma PAI-1 level...