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

Abstract

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 2,560 American Indians who were free of overt CVD and participated in the Strong Heart Family Study (SHFS) clinical exam 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. 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 ~ −0.013). This association was attenuated (β=−0.015, 95%CI: −0.029 ~ −0.002) after adjustments for demographics, study site, lifestyle (smoking, drinking, physical activity), and metabolic factors (obesity, blood pressure, fasting glucose, insulin, lipids, kidney function). Further adjustment for hsCRP did not change this association (β=−0.015, 95%CI: −0.029 ~ −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 ~ −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.

Aging, Cellular Senescence, and Alzheimer’s Disease

“…Inhibition of PAI-1 activity or deletion of the PAI-1 gene reduced brain Aβ load and improved memory in APP/PS1 mice [15,100,107,109], suggesting a pivotal role of PAI-1 in the pathophysiology of AD, although the mechanism by which PAI-1 promotes AD-liked neuropathophysiology remains unclear. Notably, PAI-1 expression is increased in many senescent cells, and increased PAI-1 has long been used as a marker of cell senescence in vitro and in vivo [13,24,[110][111][112][113]. Most importantly, accumulated evidence indicates that increased PAI-1 is not merely a marker but also a mediator of cell senescence [51][52][53][54][55][56][57].…”