Brain Ketone Bodies in Health, Evolution and Disease

Ketone bodies (KBs) are the only energy substrates oxidized by the brain, whose concentration in the circulation can greatly increase when a physiological situation requires it. For example, when an adult human fasts for two days, circulating KBs rise twenty-fold from ~0.1 to ~2 mM. As a fuel, KBs provide the brain with acetyl-CoA that produces ATP or glutamate, notably in certain brain regions. Remarkably, KBs activate the expression of their own cerebral transporters and KB-utilizing enzymes so that circulating levels determine cerebral utilization of KBs. Throughout evolution, the energetic role of KBs has been crucial for the metabolic homeostasis of humans endowed with a large brain and facing unpredictable periods of food shortage. Paradoxically, the brain of modern, regularly fed humans whose ordinary blood KBs are ~0.1 mM, has access to much fewer circulating sources of energy than that of their distant ancestors. KBs can modify certain proteins post-translationally, for example, histones through lysine-butyrylation. KBs could act as short- or long-term epigenetic messengers. These properties of KBs might allow a fetus to directly sense maternal starvation and adapt their cerebral metabolism to this situation, possibly preparing for nutritional constraints in extra-uterine life. KB transcriptional and epigenetic properties could also enable the postnatal organism to retain a molecular memory of its own starvation episodes. No other energy substrate, such as glucose or lactate, has such capacities. Medicine turned its attention to KBs a century ago. Indeed, KBs are the only energy substrates whose circulating levels can be increased, and nutritional interventions can alter them under free-living conditions. This property opens broad prospects for ketogenic diets (KDs) to prevent or rescue neurodegenerative diseases characterized by glucose hypometabolism, notably Alzheimer's disease (AD). However, KDs have not yet found real medical applications, for reasons that are discussed.