Abstract
The forkhead box protein O (FOXO, consisting of FOXO1, FOXO3, FOXO4 and FOXO6) transcription factors are the mammalian orthologues of Caenorhabditis elegans DAF-16, which gained notoriety for its capability to double lifespan in the absence of daf-2 (the gene encoding the worm insulin receptor homologue). Since then, research has provided many mechanistic details on FOXO regulation and FOXO activity. Furthermore, conditional knockout experiments have provided a wealth of data as to how FOXOs control development and homeostasis at the organ and organism levels. The lifespan-extending capabilities of DAF-16/FOXO are highly correlated with their ability to induce stress response pathways. Exogenous and endogenous stress, such as cellular redox stress, are considered the main drivers of the functional decline that characterizes ageing. Functional decline often manifests as disease, and decrease in FOXO activity indeed negatively impacts on major age-related diseases such as cancer and diabetes. In this context, the main function of FOXOs is considered to preserve cellular and organismal homeostasis, through regulation of stress response pathways. Paradoxically, the same FOXO-mediated responses can also aid the survival of dysfunctional cells once these eventually emerge. This general property to control stress responses may underlie the complex and less-evident roles of FOXOs in human lifespan as opposed to model organisms such as C. elegans.
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Acknowledgements
The authors apologize for not being able to cite all relevant studies owing to space constraints. The authors thank T. Madl (University Graz, Austria) for discussion on FOXO structure. The authors also thank all members of their respective laboratories for discussion. Research performed in the laboratories of the authors is financially supported by grants from the Dutch Cancer Foundation (KWF) (B.M.T.B., T.B.D. and M.J.R.-C.), Dutch Research Council (NWO) (M.J.R.-C.), Health Holland (B.M.T.B. and T.B.D.) and Oncode Institute (B.M.T.B.).
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Rodriguez-Colman, M.J., Dansen, T.B. & Burgering, B.M.T. FOXO transcription factors as mediators of stress adaptation. Nat Rev Mol Cell Biol 25, 46–64 (2024). https://doi.org/10.1038/s41580-023-00649-0
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DOI: https://doi.org/10.1038/s41580-023-00649-0
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