FGF21 is a multifunctional metabolic and stress hormone which is normally expressed in liver but cellular stress, e.g. mitochondrial or endoplasmic reticulum (ER) stress, can induce its expression and subsequent secretion from several mammalian tissues. The stress kinases of the integrated stress response (ISR) pathway stimulate the expression of FGF21 through the activation of ATF4 transcription factor, thus enhancing cellular stress resistance. The metabolic and stress-inducible transactivation mechanisms of FGF21 gene are mostly mediated through separate pathways. FGF21 is an interorgan regulator which can alleviate many age-related metabolic and stress disorders, e.g. through the activation of AMPK signaling. FGF21 signaling is also involved in circadian and torpor regulation. Given that circulating FGF21 can attenuate organelle stress, e.g. mitochondrial and ER stresses, it resembles a stress-induced cell non-autonomous regulation of proteostasis and longevity present in model organisms. The overexpression of FGF21 can even extend the lifespan of mice, probably by improving the healthspan. We will clarify the positive and negative signaling mechanisms which control the stress-related expression of FGF21 through the ISR pathway. Moreover, we will examine the role of FGF21 as an interorgan coordinator of survival functions in metabolic and stress disorders. We conclude that FGF21 can be viewed as a cell non-autonomous enhancer of longevity in mammals.

FGF21是一种多功能代谢和应激激素，通常在肝脏中表达，但细胞应激（例如线粒体或内质网（ER）应激）可以诱导其表达并随后从多个哺乳动物组织中分泌。整合应激反应（ISR）途径的应激激酶通过ATF4转录因子的激活来刺激FGF21的表达，从而增强细胞的抗逆性。FGF21的代谢和应激诱导反式激活机制基因主要通过单独的途径介导。FGF21是一种器官间调节剂，可通过激活AMPK信号来缓解许多与年龄有关的代谢和应激障碍。FGF21信号转导也参与昼夜节律和躯干调节。鉴于循环中的FGF21可以减轻细胞器的应激，例如线粒体和内质网应激，它类似于模型生物中存在的应激诱导的蛋白稳态和寿命的细胞非自主调节。FGF21的过表达甚至可以延长小鼠的寿命，这可能是通过提高健康寿命来实现的。我们将阐明通过ISR途径控制FGF21应激相关表达的正向和负向信号转导机制。而且，我们将研究FGF21作为代谢和应激障碍中生存功能的器官间协调者的作用。我们得出的结论是，FGF21可被视为哺乳动物中寿命的细胞非自主性增强剂。