Kyoto University study reveals new senescent cell elimination treatment which improves age-related diseases

Research on eliminating senescent cells is rapidly advancing worldwide. One approach to this—the removal of senescent cells themselves—is called 'senolysis', while the removal of only certain characteristics of senescent cells (such as chronic inflammation) is known as 'senostatics'. A research group led by Associate Professor Hiroshi Kondoh, Researcher Takumi Mikawa, and Program-Specific Assistant Professor Masahiro Kameda of the Graduate School of Medicine at Kyoto University has discovered a therapeutic drug candidate for senescent cell removal (senolysis). The researchers uncovered that in senescent cells, abnormally enhanced protein binding between the glycolytic enzyme PGAM and signal transduction kinase Chk1 increases glycolytic metabolism and promotes the survival of these cells. When the binding between PGAM and Chk1 was inhibited in mice, selective cell death (apoptosis) of senescent cells was induced, chronic inflammation was reduced, and aging-related symptoms improved. Furthermore, in mouse models of pulmonary fibrosis, an intractable age-related disease, senolysis achieved an improvement in symptoms by inhibiting PGAM-Chk1 binding. This demonstrates its effectiveness as a new treatment for age-related diseases. The results were published in Signal Transduction and Targeted Therapy.

Kondoh stated: "We found that optical isomers of Nutlin, a substance identified by Roche in 2004 as an anticancer drug candidate, have senescent cell elimination capability. In the future, we aim to advance optimal structural design and deliver this therapy to patients as soon as possible."

The researchers have studied the glycolytic enzyme PGAM from an aging perspective for many years. Using the latest NanoBit technology, they successfully visualized PGAM-Chk1 kinase binding within cells. This technology allowed them to identify enhanced glycolytic metabolism through increased PGAM-Chk1 kinase binding as a metabolic commonality between senescent cells and cancer cells. When binding inhibitors were administered to mice, aged mice displayed improvements in muscle strength and liver and kidney function.

Meanwhile, Nutlin is an anticancer drug originally developed as a p53-Mdm² binding inhibitor. It exists as Nutlin 3a and its optical isomer Nutlin 3b. It has furthermore been clarified that only Nutlin 3a has the p53-Mdm² binding inhibitory function. However, Nutlin 3a has strong side effects and was never put into practical use.

The research group uncovered Nutlin's PGAM-Chk1 binding inhibitory capability. Kondoh explained, "The results of our initial experiments showed that binding could not be inhibited by Nutlin, but by changing the analysis method, we discovered that it does have binding inhibitory capability".

The difference between Nutlin 3a and 3b exists only in their p53-Mdm² binding inhibitory capability. Both have PGAM-Chk1 binding inhibitory capability, however Nutlin 3b has the potential to eliminate senescent cells without side effects. In fact, when Nutlin 3b was administered to young cells and senescent cells respectively, 3b induced apoptosis only in senescent cells, whilst 3a showed toxicity in both young and senescent cells.

Furthermore, the group identified the transcription factor FOXM1 as a target of PGAM-Chk1 binding. Within senescent cells, FOXM1 was found to suppress the apoptosis gene BIM. When Nutlin 3b is administered, FOXM1 activity is suppressed.

Upon analyzing the FOXM1 expression pattern in aged organs, they discovered that FOXM1 is activated in the liver, lungs, kidneys, muscles, and other organs. When Nutlin 3b is administered to a model of pulmonary fibrosis, an age-related disease, both fibrosis markers and fibrotic area decreased. This illustrated its effective therapeutic effects.

Kondoh commented: "For over 30 years, I have seen various people as a general internist treating elderly patients. I still remember each and every patient. Although I could not help them, I hope to give back to future geriatric medicine based on my experiences."

Journal Information
Publication: Signal Transduction and Targeted Therapy
Title: Abrogation of aberrant glycolytic interactions eliminates senescent cells and alleviates aging-related dysfunctions
DOI: 10.1038/s41392-025-02502-6