Announcement of publication of an article on the anti-aging benefits of the PAI-1 inhibitor RS5614: Restoring cardiovascular aging

We are pleased to announce that our PAI-1 inhibitor RS5614 may restore vascular aging such as arterial stiffness, as revealed by our collaborative research with Northwestern University (USA) and Tohoku University Graduate School of Medicine (Japan), and the paper was published in The Journal of Clinical Investigation on September 30, 2025.
https://www.jci.org/articles/view/196714

The blood concentration of PAI-1 increases with age and is considered to be one of the cellular senescence-associated secretory phenomenon (SASP)¹⁾ factors. High levels of PAI-1 have been reported to be involved in various age-related diseases, such as cancer, atherosclerosis, emphysema, chronic obstructive pulmonary disease, diabetes, chronic kidney disease, osteoporosis, sarcopenia²⁾, cerebrovascular disease, and Alzheimer’s disease. Administration of PAI-1 inhibitors in these animal models has been reported to improve their pathological conditions. In this study, focusing on vascular aging, we demonstrate the involvement of PAI-1 in cardiovascular aging using genetically engineered mice and vascular aging model of mice, and confirm the benefits of our PAI-1 inhibitor RS5614 in restoring vascular aging.

We previously investigated the blood of Amish³⁾ living in the U.S. and found that some of them were deficient in the PAI-1 gene and reported that these PAI-1 gene deficient individuals have a life expectancy of about 10 years longer than those carrying the gene (Science Advances, 2017). This fact was also reported in a November 21, 2017 New York Times article (November 11, 2021). In the present study, genetically engineered mice with the same PAI-1 gene abnormality as Amish humans were generated, bred for an extended period of time, and their lifespan was measured, showing that the lifespan of PAI-1 gene-deficient mice (average lifespan of 879 days) is about 20 % longer than that of normal mice (average lifespan of 730 days).

The degree of vascular aging in normal mice and in these genetically engineered mice treated with reagents (eNOS inhibitors⁴⁾) that promote vascular aging was evaluated using systolic blood pressure (SBP: an index of peripheral vascular stiffness), pulse wave velocity (PWV; an index of arterial stiffness) and left ventricular dilatation capacity (E/e’: an index of heart (E/e’: a measure of cardiac flexibility). We found that the induction of vascular senescence observed in normal mice was attenuated in genetically engineered mice with low PAI-1 production. Conversely, age-related vascular aging was significantly accelerated in genetically engineered mice expressing high levels of PAI-1 at 12 weeks of age or older compared to normal mice.

In this study, we further analyzed the effects of RS5614 in an eNOS inhibitor-based vascular aging model. After inducing vascular aging symptoms (increased SBP and PWV) in normal mice by administering a reagent (eNOS inhibitor) that promotes vascular aging for 4 weeks, our RS5614 was administered together with the eNOS inhibitor for another 6 weeks. The results showed that RS5614 not only inhibited the progression of vascular aging induced by the eNOS inhibitor, but also improved the symptoms of vascular aging further than those before RS5614 administration. These results suggest that RS5614 has the ability to restore vascular aging once it has occurred.

As the saying goes, “one grows old with one’s blood vessels,” blood vessels age with age, and this aging of blood vessels is thought to have a significant impact on healthy life expectancy. Various lifestyle-related diseases (hypertension, diabetes, chronic kidney disease, hyperlipidemia) accelerate vascular aging. The fact that o RS5614 has been suggested to not only prevent but also restore vascular aging is extremely important.

¹⁾ Senescence-associated secretory phenomenon (SASP) factors: SASP factors are substances such as inflammatory cytokines and growth factors that are secreted in large amounts by aging cells. PAI-1 is one of SASP factors. These factors are involved in tissue repair, but also promote inflammatory responses and cause chronic inflammation.

²⁾ Sarcopenia: Sarcopenia is a condition in which muscle mass and strength decrease with age.

³⁾ Amish: Amish is an American Christian community. Epidemiological studies have shown that some of these people are deficient in the PAI-1 gene and have a long life expectancy.

⁴⁾ eNOS inhibitors : eNOS is an enzyme that produces nitric oxide (NO), which is found in vascular endothelial cells and regulates vascular tone and platelet aggregation. eNOS is essential for a healthy cardiovascular system, and its inhibitors induce vascular aging. In this paper, we use the compound L-NAME as an eNOS inhibitor.