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 levels (p<0.001). Adjusted relative leukocyte telomere length (LTL) was 10% longer in null SERPINE1 carriers (p=0.007) (Figure). Null SERPINE1 carriers had a significantly lower prevalence of diabetes mellitus (p=0.001) and 28% lower fasting insulin levels (p=0.035) compared to noncarriers. Null SERPINE1 carriers had a lower composite cardiovascular score, including pulse wave velocity, brachial pulse pressure, carotid intima-media thickness, left ventricular relaxation (e’ velocity) by 0.6 standardized units (p=0.046). In the extended Berne kindred, mean age at death in SERPINE1 carriers was delayed by 7 years compared with noncarriers (82±10 vs. 75±12 years, p=0.034).
Conclusions: Heterozygosity in SERPINE1 is associated with longer LTL, lower rate of diabetes, lower fasting insulin levels, and greater lifespan. Our findings comprise the first report of a private gene mutation in an extended kindred that is associated with parameters of aging.
Author Disclosures: S.S. Khan: None. S.J. Shah: None. E. Klyachko: None. A.S. Baldridge: None. M. Eren: None. A.T. Place: None. M. Heiman: None. S. Gupta: None. A.D. Shapiro: None. D.E. Vaughan: None.
- © 2016 by American Heart Association, Inc.