Scientists Discover New Way To Eliminate “Zombie Cells” Driving Aging

Scientists uncover a metabolic vulnerability in aging cells that could be key to restoring resilience and combating age-related diseases.

As people grow older and become more frail, their bodies often lose tissue reserve capacity. This reserve, known as resilience, allows the body to maintain homeostasis through defense, compensation, modulation, and repair processes. When resilience declines, older adults typically experience reduced daily activity along with a higher likelihood of multimorbidity, meaning the presence of multiple chronic conditions.

A key driver of this decline is the buildup of senescent cells—often called “zombie cells”—which no longer divide. The body naturally removes these cells through a process called senolysis, but this clearing system becomes less effective with age.

Senescent Cells and Inflammation

Senescent cells can damage surrounding tissue through the senescence-associated secretory phenotype, or SASP. This process involves the release of pro-inflammatory molecules that disrupt nearby cells. Over time, this contributes to chronic inflammation and the progression of age-related diseases, helping explain the loss of resilience seen in older individuals. However, the connection between metabolic resilience, survival capacity, and SASP has not been fully understood.

To explore this, researchers at Kyoto University examined how senescent cells function at a molecular level. They found that these cells rely heavily on glycolysis, the process of breaking down glucose for energy, a trait also seen in cancer cells. The team focused on two molecules involved in this process: phosphoglycerate mutase (PGAM), a glycolytic enzyme, and Chk1 kinase, which bind together in cancer cells to boost glycolysis.

Investigating Metabolic Mechanisms

To study whether this interaction also occurs in senescent cells, the researchers developed a NanoBiT assay, a method that uses bioluminescence to detect protein interactions. Their results showed that PGAM-Chk1 binding is increased in senescent cells, supporting both glycolysis and cell survival. When this interaction was blocked, senescent cells were selectively eliminated in both in vitro and in vivo experiments. The approach also reduced lung fibrosis in mice.

The study further revealed that this molecular interaction affects FoxM1, a transcription factor that plays a central role in the cell cycle. FoxM1 was found to suppress BIM, a protein that triggers apoptosis, or programmed cell death. It also activates DNA repair systems in senescent cells. Disrupting PGAM-Chk1 binding may therefore limit FoxM1 activity, allowing damaged cells to undergo apoptosis and potentially slowing the decline in resilience.

Implications for Senotherapy

These findings could have clinical relevance for senotherapy, an emerging approach aimed at treating age-related diseases by targeting senescent cells. The results may also support the development of senolytics, therapies designed to eliminate these cells by inducing apoptosis.

“Our findings in glycolytic regulation suggest that impaired metabolic resilience in aging is one of the targets for senotherapy, to aid in preservation of resilience in aging,” says corresponding author Hiroshi Kondoh.

Reference: “Abrogation of aberrant glycolytic interactions eliminates senescent cells and alleviates aging-related dysfunctions” by Takumi Mikawa, Masahiro Kameda, Sumiko Ikari, Eri Shibata, Shuyu Liu, Sawa Miyagawa, Koh Ono, Tomiko Ito, Akihiko Yoshizawa, Masataka Sugimoto, Shuichi Shibuya, Takahiko Shimizu, Julio Almunia, Noboru Ogiso, Gwladys Revêchon, Alberta Palazzo, David Bernard, Hiroaki Kanda, Tomoyoshi Soga, Keiyo Takubo, Shin Morioka, Junko Sasaki, Takehiko Sasaki, Akihiro Itamoto, Takayuki Fujii, Hiroshi Seno, Nobuya Inagaki and Hiroshi Kondoh, 15 December 2025, Signal Transduction and Targeted Therapy.
DOI: 10.1038/s41392-025-02502-6

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