TY - JOUR
T1 - A null mutation in SERPINE1 protects against biological aging in humans
AU - Khan, Sadiya S.
AU - Shah, Sanjiv J.
AU - Klyachko, Ekaterina
AU - Baldridge, Abigail S.
AU - Eren, Mesut
AU - Place, Aaron T.
AU - Aviv, Abraham
AU - Puterman, Eli
AU - Lloyd-Jones, Donald M.
AU - Heiman, Meadow
AU - Miyata, Toshio
AU - Gupta, Sweta
AU - Shapiro, Amy D.
AU - Vaughan, Douglas E.
N1 - Funding Information:
We thank our Amish liaisons and the Indiana Hemophilia and Thrombosis Center’s Research clinic staff, as well as the Feinberg Cardiovascular Research Institute volunteers. In addition, we extend our deepest gratitude to the Berne Amish community for their time, participation, and support, without which these studies would not have been possible. A pedigree is also included in the Supplementary Materials and is abbreviated to provide anonymity. We thank the participants of the CARDIA study for their long-term commitment and important contributions to the study. Funding: This work was supported by grants from the NIH (R01 HL051387 to D.E.V.; F32 HL129695 to S.S.K.; R01 HL127028 and HL107577 to S.J.S.; and R01HD071180, R01HL116446, and R01HL134840 to A.A.). The CARDIA is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201300025C and HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also supported, in part, by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). This manuscript has been reviewed by CARDIA for scientific content. Author contributions: D.E.V., S.S.K., and S.J.S. provided substantial contribution to the conception and design of the study, data acquisition and analysis, and drafting and critical revision of the manuscript. A.S.B. contributed to data analysis and critical manuscript revisions. E.K., M.E., A.T.P., D.M.L.-J., E.P., A.A., T.M., and M.H. contributed to data acquisition and critical revision of the manuscript. S.G. and A.D.S. contributed substantially to the conception and design of the study, data acquisition, and critical revision of the manuscript. All coauthors approved the final version of the manuscript to be published and agreed to be accountable for the accuracy and integrity of all aspects of the work. D.E.V. claims responsibility for all figures in the manuscript and the Supplementary Materials. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.
Publisher Copyright:
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
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U2 - 10.1126/sciadv.aao1617
DO - 10.1126/sciadv.aao1617
M3 - Article
C2 - 29152572
AN - SCOPUS:85041920653
SN - 2375-2548
VL - 3
JO - Science advances
JF - Science advances
IS - 11
M1 - eaao1617
ER -
