Integrated stress response stimulates FGF21 expression: Systemic enhancer of longevity.

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.