Integrated stress response stimulates FGF21 expression: Systemic enhancer of longevity

Area of Science:

• Endocrinology
• Metabolic regulation
• Cellular stress response

Background:

• Fibroblast growth factor 21 (FGF21) is a hormone typically produced in the liver.
• Cellular stress, including mitochondrial and endoplasmic reticulum (ER) stress, can induce FGF21 expression in various tissues.
• The integrated stress response (ISR) pathway, via ATF4, stimulates FGF21 production to bolster cellular stress resistance.

Purpose of the Study:

• To elucidate the signaling mechanisms controlling stress-induced FGF21 expression through the ISR pathway.
• To investigate FGF21's role as an interorgan regulator in metabolic and stress-related disorders.
• To explore FGF21's potential as a longevity enhancer.

Main Methods:

• Analysis of integrated stress response (ISR) pathway signaling.
• Investigation of FGF21 gene transactivation mechanisms.
• Examination of FGF21's role in interorgan communication and metabolic regulation.

Main Results:

• FGF21 expression is stimulated by cellular stress via the ISR pathway and ATF4.
• FGF21 acts as an interorgan regulator, alleviating metabolic and age-related stress disorders.
• FGF21 signaling is implicated in circadian rhythms and torpor regulation.

Conclusions:

• FGF21 mitigates organelle stress and promotes proteostasis and longevity.
• Overexpression of FGF21 in mice has been linked to extended lifespan and improved healthspan.
• FGF21 functions as a cell non-autonomous enhancer of longevity in mammals.