Practical prospects for boosting hepatic production of the “pro-longevity” hormone FGF21

Fibroblast growth factor-21 (FGF21), produced mainly in hepatocytes and adipocytes, promotes leanness, insulin sensitivity, and vascular health while down-regulating hepatic IGF-I production. Transgenic mice overexpressing FGF21 enjoy a marked increase in median and maximal longevity comparable to that evoked by calorie restriction - but without a reduction in food intake. Transcriptional factors which promote hepatic FGF21 expression include PPARα, ATF4, STAT5, and FXR; hence, fibrate drugs, elevated lipolysis, moderate-protein vegan diets, growth hormone, and bile acids may have potential to increase FGF21 synthesis. Sirt1 activity is required for optimal responsiveness of FGF21 to PPARα, and Sirt1 activators can boost FGF21 transcription. Conversely, histone deacetylase 3 (HDAC3) inhibits PPARα's transcriptional impact on FGF21, and type 1 deacetylase inhibitors such as butyrate therefore increase FGF21 expression. Glucagon-like peptide-1 (GLP-1) increases hepatic expression of both PPARα and Sirt1; acarbose, which increases intestinal GLP-1 secretion, also increases FGF21 and lifespan in mice. Glucagon stimulates hepatic production of FGF21 by increasing the expression of the Nur77 transcription factor; increased glucagon secretion can be evoked by supplemental glycine administered during post-absorptive metabolism. The aryl hydrocarbon receptor (AhR) has also been reported recently to promote FGF21 transcription. Bilirubin is known to be an agonist for this receptor, and this may rationalize a recent report that heme oxygenase-1 induction in the liver boosts FGF21 expression. There is reason to suspect that phycocyanorubin, a bilirubin homolog that is a metabolite of the major phycobilin in spirulina, may share bilirubin's agonist activity for AhR, and perhaps likewise promote FGF21 induction. In the future, regimens featuring a plant-based diet, nutraceuticals, and safe drugs may make it feasible to achieve physiologically significant increases in FGF21 that promote metabolic health, leanness, and longevity.