Increased PAI-1 Expression Contributes to Degenerative Aging
Researchers here review what is known of the role of PAI-1 in aging. A small number of humans are known to exhibit loss of function mutations in PAI-1, indicating that the activities of PAI-1 are not vital to life. While the known population is very small, and thus there is a great deal more uncertainty as to whether the existing data is representative of how this would work in a broader population, it appears that these individuals may live 7 years longer than their peers. On some time frame the research community will likely develop therapies to inhibit PAI-1 expression or activity, but is worth remembering that therapies inspired by a beneficial mutation usually provide only a fraction of the benefits of that mutation - because they are only partially inhibiting the gene or protein, because a patient only takes the therapy for a few years rather than a lifetime, and so forth.
Plasminogen activator inhibitor-1 (PAI-1), encoded by the SERPINE1 gene, is a serine protease inhibitor primarily recognized for its role in regulating fibrinolysis by inhibiting plasminogen activators which facilitate the conversion of plasminogen into plasmin. Subsequently, active plasmin breaks down fibrin, which is an integral meshwork of blood clots. Hence, PAI-1 effectively slows down or prevents clot breakdown. Beyond this hemostatic function, PAI-1 has emerged as a culprit in contributing to aging and age-related diseases.
A significant body of literature outlines PAI-1's involvement in cellular senescence, inflammation, and tissue remodeling. Elevated PAI-1 levels are consistently observed in conditions such as cardiovascular disease, metabolic syndrome, cancer, and neurodegeneration, suggesting it plays an active role in the aging process. Studies across species demonstrate that circulating PAI-1 level increases progressively with chronological age, paralleling the accumulation of senescent cells and the onset of age-related pathologies. For instance, longitudinal analyses in human cohorts reveal a steep rise in plasma PAI-1 levels after middle age, correlating with increased cardiovascular risk and frailty. This temporal correlation implies PAI-1 may be an active participant in aging, and not merely a passive marker.
Although previous reviews have extensively covered PAI-1 in the context of cardiovascular disease, cancer, and metabolic dysfunction, this review integrates recent evidence with seminal articles in the literature to provide evidence for the model that PAI-1 is not only involved in age-related conditions but is a central driver of the aging process itself. A rare loss-of-function SERPINE1 mutation in humans extends lifespan, illustrating how lifelong PAI-1 reduction can positively impact the human healthspan. Looking forward, targeting PAI-1 with inhibitors could mitigate senescence, restore stem cell function, improve metabolic profile, enhance physiological health, and promise a longer healthspan.