FOXO蛋白（包括FOXO1、FOXO3、FOXO4和FOXO6）是线虫DAF-16的哺乳动物同源物，DAF-16因其在daf-2（编码线虫胰岛素受体同源基因）缺失时能使寿命加倍而出名。此后，研究已提供了关于FOXO调控和活性的许多机制细节。此外，有条件敲除实验已提供了FOXO如何控制器官和有机体水平的发育和稳态的大量数据。DAF-16/FOXO能够延长寿命的能力与其诱导应激反应途径的能力密切相关。细胞内外的应激，如细胞氧化还原应激，被认为是衰老引起的功能下降的主要驱动因素。功能下降通常表现为疾病，并且FOXO活性的降低确实会对癌症和糖尿病等主要年龄相关疾病产生负面影响。在这种情况下，FOXO的主要功能被认为是通过调节应激反应途径来维持细胞和有机体的稳态。矛盾的是，同样由FOXO介导的应答反应也可以在这些异常细胞最终出现时有助于其存活。这种对应激反应的控制通用性可能是解释FOXO在人类寿命中复杂和不明显角色的基础，与C. elegans等模式生物不同。 © 2023. Springer Nature Limited.

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.© 2023. Springer Nature Limited.