Autophagy is a fundamental cellular process that maintains homeostasis by degrading damaged proteins and organelles. Dysregulated autophagy is associated with various age-related diseases, including neurodegenerative disorders and cancer. Alpha-ketoglutarate (AKG) is a Krebs cycle intermediate that has been shown to have anti-aging and neuroprotective effects. However, the role of AKG in autophagy regulation is not well understood..
In this study, we investigated the effects of AKG on autophagy and inflammation in Caenorhabditis elegans. We found that AKG treatment increased autophagic activity, as evidenced by increased expression of autophagy-related genes and proteins, and accumulation of autophagosomes. AKG also inhibited inflammation, as indicated by decreased expression of inflammatory cytokines and reduced production of reactive oxygen species (ROS)..
Mechanistically, AKG increased autophagy by activating the AMPK-ULK1 pathway. AMPK is a kinase that promotes autophagy, while ULK1 is a kinase that initiates autophagosome formation. AKG treatment increased AMPK activity and phosphorylation of ULK1, suggesting that AKG activates autophagy through the AMPK-ULK1 pathway..
In addition, AKG inhibited inflammation by reducing the production of ROS. ROS are known to activate the NF-κB pathway, which promotes inflammation. AKG treatment reduced ROS production and inhibited NF-κB activity, suggesting that AKG inhibits inflammation through the reduction of ROS production and inhibition of the NF-κB pathway..
Our findings demonstrate that AKG is a potent inducer of autophagy and inhibitor of inflammation in C. elegans. AKG activates autophagy through the AMPK-ULK1 pathway and inhibits inflammation through the reduction of ROS production and inhibition of the NF-κB pathway. These findings suggest that AKG may be a potential therapeutic agent for the treatment of age-related diseases characterized by dysregulated autophagy and inflammation..
