The role of FGF21 in aging and aging-related diseases

Aging and aging-related diseases represent an increasing burden on modern society. Thus, drugs that retard the aging process are highly desirable. Fibroblast growth factor-21 (FGF21) is a hormone secreted by the liver during fasting that elicits diverse aspects of the adaptive starvation response. Among its effects, FGF21 induces hepatic fatty acid oxidation and ketogenesis, increases insulin sensitivity and blocks somatic growth. Here we show that transgenic overexpression of FGF21 markedly extends lifespan in mice without reducing food intake or affecting AMP kinase or mTOR signaling or NAD metabolism. Transcriptomic analysis suggests that FGF21 acts primarily by blunting the growth hormone/insulin-like growth factor-1 signaling pathway in liver. These findings raise the possibility that FGF21 can be used as a hormone therapy to extend lifespan. Liver, epididymal fat and gastrocnemius muscle RNA expression profiles were compared between C57Bl/6J ad libitum, fasted, and calorically restricted mice, as well as between FGF-21 transgenic and their wild-type C57Bl/6J controls.衰老与衰老相关疾病正日益成为现代社会的沉重负担，因此，能够延缓衰老进程的药物具有极高的研发与应用价值。 成纤维细胞生长因子-21（Fibroblast growth factor-21, FGF21）是禁食状态下肝脏分泌的一种激素，可介导适应性饥饿反应的多种生物学效应。其已知效应包括诱导肝脏脂肪酸氧化与酮体生成、提升胰岛素敏感性并抑制躯体生长。 本研究证实，转基因过表达FGF21可显著延长小鼠寿命，且不会降低进食量，也不会影响AMP激酶（AMP kinase）、mTOR信号通路及烟酰胺腺嘌呤二核苷酸（NAD）代谢。 转录组分析结果显示，FGF21主要通过抑制肝脏内生长激素/胰岛素样生长因子-1（insulin-like growth factor-1, IGF-1）信号通路发挥作用。 本研究结果提示，FGF21有望作为激素疗法用于延长机体寿命。 本研究对自由进食、禁食及热量限制的C57Bl/6J小鼠，以及FGF21转基因小鼠与其野生型C57Bl/6J对照小鼠的肝脏、附睾脂肪及腓肠肌的RNA表达谱进行了比较。