Formononetin fights cellular aging via FOS-driven pathway

Aging has long been framed as an irreversible decline, a one-way street at the cellular level. But a new study published in the journal Biogerontology suggests that at least some of the hallmarks of cellular aging may be negotiable. Researchers in South Korea report that formononetin, a plant-derived isoflavone found in legumes and traditional medicinal herbs, can coax senescent cells back into active proliferation while simultaneously restoring the function of their failing mitochondria. Crucially, they identified the mechanism behind this rejuvenation: a surge in the expression of a gene called FOS, a long-suspected but elusive player in the biology of senescence.

Cellular senescence is a state in which a cell permanently exits the cell cycle. It is not death, but a kind of suspended animation—cells remain metabolically active, yet they refuse to divide. Senescence serves important purposes, including suppression of tumor formation and participation in wound healing, but the accumulation of senescent cells in tissues over time is increasingly recognized as a driver of aging and age-related disease. Senescent cells secrete inflammatory molecules, degrade surrounding tissue structure, and, as the new study highlights, suffer from profound mitochondrial dysfunction. The team, led by Minseon Kim and Joon Tae Park of Incheon National University together with Youngjoo Byun and Ki Yong Lee of Korea University, set out to find compounds that could reverse this state rather than simply kill the cells carrying it.

The approach began with a screen of plant-derived secondary metabolites, the chemically diverse small molecules that plants produce for defense and signaling. Secondary metabolites have attracted growing attention in the anti-aging field because they are structurally diverse, evolutionarily honed, and often capable of modulating mammalian signaling pathways at low concentrations. From this library, formononetin emerged as a standout: it potently induced the proliferation of senescent fibroblasts, the connective tissue cells that are among the most studied models of replicative aging. Fibroblasts are particularly relevant to aging biology because their senescence is implicated in skin aging, impaired wound healing, and age-related pigmentation changes.

To understand how formononetin achieved this apparently paradoxical effect—forcing a cell that had locked itself out of the cell cycle to divide again—the researchers examined the molecular brakes that enforce senescence. Two of the most important are the tumor suppressor genes p53 and Rb-1. The p53 protein acts as a guardian of the genome, halting cell division when damage is detected, while the retinoblastoma protein (Rb-1) blocks the transcription factors that cells need to launch DNA replication. In senescent cells, these pathways are locked in an “on” position. After formononetin treatment, the team found that expression of these key cell cycle inhibitors was suppressed, effectively loosening the brakes and permitting cell cycle re-entry.

The second half of the story concerns mitochondria. Senescent cells typically exhibit damaged, inefficient mitochondria that leak reactive oxygen species, contributing to both the maintenance of the senescent state and the inflammation that aging tissues endure. When the researchers measured mitochondrial function in formononetin-treated cells, they found a striking restoration: the proliferative response was accompanied by a recovery of mitochondrial performance. This detail matters because a growing body of work argues that mitochondria are not merely victims of senescence but active participants in establishing and maintaining it. A compound that addresses both the cell cycle arrest and the energetic collapse of senescent cells is therefore attacking the phenomenon from two directions at once.

The decisive clue came from transcriptome analysis, the global survey of gene expression that reveals which programs a cell has switched on or off in response to a treatment. Among the genes responding to formononetin, one stood out: the Fos proto-oncogene, or FOS. FOS encodes c-Fos, a transcription factor that pairs with members of the Jun family to form AP-1, a transcriptional complex that drives the expression of genes needed for cells to exit quiescence and begin dividing. The connection to aging is not new—decades ago, researchers showed that c-fos transcription is repressed in senescent human fibroblasts, and that AP-1 activity is required to initiate DNA synthesis. But reviving that lost program with a small molecule, and showing that it is sufficient to reproduce the anti-senescence effects, is a significant step forward.

To verify that FOS was not merely a bystander, the team performed functional tests demonstrating that artificially increasing FOS expression recapitulated the anti-senescence effects of formononetin. In other words, FOS appears to be a downstream regulator through which the compound exerts its influence. When FOS expression rises, senescent cells regain the transcriptional license to re-enter the cell cycle, and their mitochondria recover. This mechanistic clarity elevates the finding beyond a simple observation that a plant compound makes old cells divide; it identifies a specific, targetable node in the senescence network.

The implications cut in two directions, and the authors are careful about both. On the optimistic side, the study suggests that therapeutic strategies regulating the formononetin-mediated FOS pathway could be promising treatments for aging and age-related diseases. Formononetin itself has a favorable preliminary profile: it is a dietary isoflavone with documented anti-inflammatory and antioxidant activities, and it is already consumed as part of normal diets in legume-rich regions. Unlike senolytics, which kill senescent cells and must be deployed with care because senescence also performs tumor-suppressive and wound-healing functions, a senomorphic approach that modulates the state of senescent cells—restoring function without necessarily deleting them—offers a different therapeutic logic. Restoring mitochondrial health and proliferative capacity in tissue-resident cells such as fibroblasts could, in principle, improve skin structure, wound repair, and other functions that decline with age.

On the cautious side, reactivating proliferation in senescent cells raises the question of oncogenic risk. FOS is, after all, classified as a proto-oncogene, and p53 and Rb-1 are the cell’s principal defenses against uncontrolled division. Suppressing these brakes in aged tissue is precisely the kind of intervention that would need to be calibrated with great precision. The researchers frame their work as revealing a previously unknown mechanism—cell cycle re-entry and mitochondrial restoration through FOS regulation—rather than as a ready-made therapy. The experiments were conducted in cell culture models, and translating them into safe treatments will require animal studies, dosing optimization, and careful assessment of whether partially rejuvenated cells retain genomic integrity. Senescent cells accumulate DNA damage over time, and any strategy that encourages them to divide must ensure that damaged genomes are not propagated.

Even with those caveats, the study adds a valuable entry to a growing catalog of natural products with anti-senescence activity. The same group and others have previously identified plant compounds that reduce mitochondrial ROS production or modulate senescence through other targets, and the field has moved steadily from broad observations toward defined molecular mechanisms. What distinguishes the present work is the convergence of three threads—proliferation rescue, mitochondrial restoration, and a single named regulator connecting them—arrived at through an unbiased screen followed by rigorous functional validation.

The work was supported by the National Research Foundation of Korea, and the authors report no conflicts of interest. The study was received in June 2026, accepted in August, and published on 24 August 2026 in Biogerontology, volume 27. For a field that has long treated senescence as an endpoint, the message of the paper is quietly radical: with the right molecular key—in this case, one derived from plants and acting through an old transcription factor—the lock can apparently be turned. Whether that key can be safely applied in living organisms remains the question the next decade of research must answer, but for now, the demonstration that formononetin can rewind key features of the senescent state through FOS gives aging researchers a new and actionable target.