Review: FoxM1 was activated in young mice and inhibited in old mice, with the intervention depending on the tissue and cell type
Review: FoxM1 was activated in young mice and inhibited in old mice, with the intervention depending on the tissue and cell type
A review by a Kyoto University group compared two studies of FoxM1, a protein that regulates cell division and DNA repair programs. One study briefly activated FoxM1 in mice starting at a young age. The other inhibited it in very old mice, eliminating some senescent cells. The authors attribute the different outcomes to age, organ, and cell type.
On August 17, a review by Takumi Mikawa and colleagues compared these findings. Senescent cells stop dividing but remain in tissues and release inflammatory signals. FoxM1 may support their survival. When briefly activated from a young age, it may instead support tissue repair programs.
In a 2022 study, researchers activated an introduced, constitutively active form of FoxM1 in mice starting at eight weeks of age. It was active for three days, followed by a four-day pause, and this cycle continued for a total of 80 weeks. The authors reported that this treatment reduced age-related features and extended lifespan in both progeroid and naturally aging animals.
In a 2025 paper, the authors investigated the interaction between PGAM1 and Chk1 in senescent cells. PGAM1 is an enzyme involved in glucose metabolism, while Chk1 contributes to the cellular response to DNA damage. Their interaction stabilized HIF-2α, a regulator of genes involved in glucose metabolism, and increased FoxM1 activity. This provided the cells with material for nucleotide synthesis. Nucleotides are the building blocks of DNA, and their production supported the cell survival program. Nutlin-3b disrupted this interaction. Senescent fibroblasts and macrophages underwent programmed cell death, whereas senescent endothelial cells did not respond to the treatment.
Nutlin-3a, which has a similar structure, activated p53, a protein that can induce cell death after DNA damage, and also killed young cells. A comparison of the two compounds linked the selectivity of Nutlin-3b to the PGAM1–Chk1 axis. In 20-month-old mice, weekly Nutlin-3b injections for three months improved performance in a wire-hanging test and reduced markers of senescence in the lungs, liver, and kidneys. In these organs, the authors also found that FoxM1 expression increased again in old mice. It remained reduced in the heart, white adipose tissue, and brain.
The review authors propose selecting the direction of FoxM1 modulation according to age, organ, and senescent cell type. Early pulses of FoxM1 activity and later inhibition of the PGAM1–Chk1 axis were effective under different biological conditions.