Announcement of Publication of a Paper on the Anti-Aging Effects of PAI-1 Inhibitor RS5614: Enhancement of the immune system’s ability to remove “damaged and senescent cells” (efferocytosis).

We are pleased to announce that one of the mechanisms of action for the anti-aging benefits of our PAI-1 inhibitor RS5614 has been elucidated through collaborative research with Tokai University School of Medicine and Tohoku University Graduate School of Medicine, and was published in Cell Death Discovery , 12:195 on May 6, 2026.

https://www.nature.com/articles/s41420-026-03076-0

It has been demonstrated that the PAI-1 inhibitor RS5614 suppresses tissue damage associated with inflammation and aging. However, its mechanism of action had not been fully elucidated. Macrophages¹⁾ accumulate in tissues associated with inflammation and aging-related diseases and play a crucial role in removing “damaged and senescent cells.” PAI-1 is produced in large quantities in damaged and senescent cells, forming a barrier against immune system components, thereby reducing the macrophages’ ability to remove damaged and senescent cells (efferocytosis). On the other hand, it was suggested that the PAI-1 inhibitor RS5614 enhances the macrophages’ ability to remove damaged and senescent cells, thereby improving tissue damage associated with inflammation and aging.

This study, using a mouse skeletal muscle injury model, first revealed that cells accumulating at the site of inflammation strongly produce PAI-1. Furthermore, by using genetic modification and cell transfer techniques to eliminate PAI-1, we demonstrated that PAI-1 enhances injury and prolongs inflammation. Notably, administration of the PAI-1 inhibitor RS5614 significantly improved skeletal muscle injury. This finding suggests that RS5614 may have one mechanism of action to improve tissue damage associated with inflammation and aging, supporting the anti-aging benefits of RS5614.

The removal of injured and senescent cells by macrophages is called ‘efferocytosis’. Injured and senescent cells express a protein called calreticulin (CRT)²⁾ on their cell surface, which is recognized and removed via the LDL receptor protein LRP 1 on the surface of macrophages. This study revealed that PAI-1 binds more strongly to LRP1 than CRT and competes with CRT, thereby suppressing CRT-mediated cell removal. Notably, the PAI-1 inhibitor RS5614 enhances this macrophage-mediated ‘efferocytosis’ by inhibiting PAI-1, promoting the removal of damaged and senescent cells.

The novel mechanism of action of PAI-1 inhibitors revealed in this study suggests that they may also be involved in the progression of other inflammatory diseases, cancer, and age-related diseases. While previous studies have shown that PAI-1 inhibitors enhance cancer immunity, these results strongly suggest that they may also enhance immunity against damaged and senescent cells.

¹⁾ Macrophage: These are cells of the immune system that engulf and digest foreign substances such as invading bacteria, playing a major role in the body’s defense. They also play an important role in removing damaged cells, senescent cells, and cancer cells within the body.

²⁾ Calreticulin (CRT): This protein is expressed in damaged cells, senescent cells, and cancer cells and promotes phagocytosis by macrophages (efferocytosis). It is one of the signals that says, “Eat me.”