Abstract

Exercise enhances mitophagy to reduce cytosolic mtDNA release and inhibit cGAS-STING pathway activation. • Hepatic FGF21 is essential for exercise-induced hippocampal mitophagy and neuroprotection. • FGF21 restores microglial lysosomal function and mitophagy via the AMPK-TFEB signaling. Aging-associated neuroinflammation is a major contributor to cognitive decline, and exercise is an effective non-pharmacological intervention against it. However, the molecular mechanisms linking peripheral adaptations to exercise with central neuroprotection in the aged brain remain incompletely understood. In this study, using aged male C57BL/6J mice subjected to 16-week treadmill exercise, we show that aerobic exercise improves cognitive function and attenuates hippocampal neuroinflammation. Through bioinformatic analysis, we identified fibroblast growth factor 21 (FGF21) as an exercise-induced yet aging-suppressed hepatokine. Notably, hepatic FGF21 knockdown eliminated the capacity of exercise to enhance hippocampal mitophagy, along with its beneficial effects on cognition and neuroinflammation. Pharmacological blockade of mitophagy recapitulated the loss of FGF21 function, similarly abolishing the exercise-induced cognitive improvements and attenuation of neuroinflammation. These findings suggest that the neuroprotective effects of FGF21 may be mediated through the promotion of mitophagy. Mechanistically, FGF21 activated the AMPK-transcription factor EB (TFEB) axis in microglia to restore lysosomal function and mitophagy. Restoration of microglial mitophagy was accompanied by reduced cytosolic mtDNA accumulation and attenuated cGAS-STING-driven neuroinflammation in the aged hippocampus. Together, our findings reveal a liver-brain axis through which exercise-induced hepatic FGF21 reshapes microglial homeostasis in the aging brain, and identify FGF21 as a potential therapeutic target for age-related cognitive decline.