Formononetin attenuates cellular senescence through a FOS-mediated mechanism

Cellular senescence is characterized by cell cycle arrest accompanied by mitochondrial dysfunction. Despite extensive efforts to overcome this stable state of growth arrest, effective strategies for treating cellular senescence have not been identified. In this study, we screened plant-derived secondary metabolites and confirmed that formononetin is a substance that potently induces the proliferation of senescent fibroblasts. Formononetin-induced proliferation was associated with the suppression of expression of key cell cycle inhibitors, including p53 and Rb-1. This proliferative response was accompanied by the restoration of mitochondrial function. Transcriptome analysis identified the Fos proto-oncogene (FOS) as a downstream regulator, and FOS expression significantly increased after formononetin treatment. Functional verification further confirmed that the increase in FOS expression recapitulates the anti-senescence effects of formononetin. In summary, the results of this study revealed a previously unknown mechanism by which formononetin promotes cell cycle re-entry and restores mitochondrial function through the regulation of FOS expression. These findings suggest that therapeutic strategies regulating formononetin-mediated FOS pathway could be promising treatments for aging and age-related diseases.