Ketosis May Promote Brain Macroautophagy via Activation of Hypoxia- Inducible Factor-1

Ketogenic diets are markedly neuroprotective, but the basis of this effect is still poorly understood. Recent studies demonstrate that ketone bodies increase neuronal levels of hypoxiainducible factor-1α (HIF-1α), possibly owing to succinate-mediated inhibition of prolyl hydroxylase activity. Another recent study has observed reduced activity of mTORC1 in the cortex of rats fed a ketogenic diet. These effects could be expected to collaborate in the induction of neuronal autophagy. Considerable evidence points to moderate up-regulation of neuronal autophagy as a rational strategy for prevention of neurodegenerative disorders; hence, autophagy may mediate some of the neuroprotective benefits of ketogenic diets. Brainpermeable agents which activate AMP-activated kinase, such as metformin and berberine, can also boost neuronal autophagy, and may have potential for amplifying the impact of ketogenesis on this process. Since it would not be practical for most people to adhere to ketogenic diets continuously, alternative strategies are needed to harness the brain-protective potential of ketone bodies. These may include ingestion of medium-chain triglycerides, intermittent ketogenic dieting, and possibly the use of supplements that promote hepatic ketogenesis – notably carnitine and hydroxycitrate – in conjunction with dietary regimens characterized by long daily episodes of fasting or carbohydrate avoidance.