Plasminogen activator inhibitor-1 is associated with leukocyte telomere length in American Indians: findings from the Strong Heart Family Study

Abstract

Essentials Plasminogen activator inhibitor-1 (PAI-1) advanced cellular senescence in experiment studies. No population study exists on the association between PAI-1 and biological aging in American Indians. We found cross-sectional and longitudinal associations between higher PAI-1 and shorter telomere length. Our findings suggest a pathway linking PAI-1 with biological aging beyond metabolic factors.

Summary: Background Plasminogen activator inhibitor-1 (PAI-1) promotes cellular aging both in vitro and in vivo. Telomere length is a marker of biological aging. Objectives To examine the cross-sectional and longitudinal associations between plasma PAI-1 and leukocyte telomere length in a large-scale epidemiological study of American Indians. Methods We measured leukocyte telomere length (LTL) and plasma PAI-1 in 2560 American Indians who were free of overt cardiovascular disease (CVD) and participated in the Strong Heart Family Study (SHFS) clinical examination in 2001-2003. LTL and PAI-1 were repeatedly measured in 475 participants who attended SHFS clinical visits in both 2001-2003 and 1998-1999. A generalized estimating equation model was used to examine the cross-sectional and longitudinal associations between PAI-1 and LTL, adjusting for known risk factors. Results A higher level of plasma PAI-1 was negatively associated with shorter age-adjusted LTL (β = -0.023; 95% CI, -0.034 to -0.013). This association was attenuated (β = -0.015; 95% CI, -0.029 to -0.002) after adjustments for demographics, study site, lifestyle (smoking, drinking and physical activity) and metabolic factors (obesity, blood pressure, fasting glucose, insulin, lipids and kidney function). Further adjustment for hsCRP did not change this association (β = -0.015; 95% CI, -0.029 to -0.001). Longitudinal analysis revealed that change in plasma PAI-1 was also inversely associated with change in LTL after adjusting for demographics, follow-up years, lifestyle factors, changes in metabolic factors, baseline levels of PAI-1 and LTL (β = -0.0005; 95% CI, -0.0009 to -0.0001). Conclusions A higher level of plasma PAI-1 was associated with shorter LTL in American Indians. This finding may suggest a potential role of PAI-1 in biological aging among American Indians.

Keywords: Indians, South American; aging; fibrinolysis; plasminogen activator inhibitor 1; telomere; thrombosis.

Figure 1

Flowchart illustrating the study design of SHFS and the selection of study participants. The Strong Heart Family Study (SHFS) was initiated in 1997 by enrolling 967 family members of the original cohort, and then expanded in 2001–2003 by enrolling a total of 3,665 participants from 94 families including the re-examination of most of the 967 family members. The current analysis excluded 874 participants because one community withdrew consent for continuing participating in the study. After further excluding participants with overt CVD and missing data on either PAI-1 or LTL, a total of 2,560 participants were included in the cross-sectional analysis and 475 participants were included in the longitudinal analysis.