During periods of low glucose availability, e.g., fasting, ketogenic diet, or long-duration exercise, the endogenous (in-the-body) production of ketone bodies increases to maintain an adequate supply of energy. Ketone bodies like beta-hydroxybutyrate act as a transportable form of acetyl-CoA that can be converted into adenosine triphosphate (ATP) in organs of the body.[1][2][3][4] Beta-hydroxybutyrate can also regulate gene expression, neuronal function, and metabolic rate, either directly or indirectly through the metabolites into which it is converted.[2][5][4] Furthermore, beta-hydroxybutyrate can inhibit the activity of histone deacetylases, which means it may play a role in epigenetics, a process where modifications to DNA regulate whether genes are turned on or off.[2][5][4] Consequently, because consuming exogenous ketones[6][7][8][9] (including ketone precursors like 1,3-butanediol)[10][11][12] increases the circulating concentration of beta-hydroxybutyrate in the blood, exogenous ketones could provide energy to the body and regulate gene expression, etc.
How do exogenous ketones improve cognitive function?
Because exogenous ketones increase beta-hydroxybutyrate levels, it is plausible that they provide an additional source of energy for the brain during periods of high energy demand, like during stressful cognitive tasks.[3][13][14] Additionally, intravenous infusion of beta-hydroxybutyrate in humans has been shown to increase blood flow and oxygen uptake in the brain,[15] which might help improve nutrient and oxygen delivery to the brain during cognitive tasks. Studies in rodents and other preclinical models have also shown that ketones can reduce inflammation in the brain by blunting the release of glutamate from astrocytes (cells in the central nervous system).[16]
How do exogenous ketones improve glycemic control?
Meta-analyses have found that exogenous ketones can increase serum insulin,[8][7] a hormone that increases glucose uptake, which potentially explains how ketones can lower blood glucose. However, clinical studies have also shown that ketones can decrease the blood concentrations of alanine,[17] which is a precursor for gluconeogenesis (the production of new glucose). This is relevant because reducing gluconeogenesis would lower the amount of glucose released by the liver into the blood and thus lower blood glucose.
How do exogenous ketones improve cardiac function?
By raising beta-hydroxybutyrate levels in the blood, exogenous ketones might provide an additional source of energy for the contractile muscles in the heart to help increase the left ventricular ejection fraction and cardiac output in people with heart failure.[18] Furthermore, in vitro studies in cardiac muscle cells have shown that ketone bodies can regulate the production of reactive oxygen species,[4][19][20] which are involved in oxidative stress. However, the precise mechanisms for the effect of exogenous ketones on cardiac function and other outcomes, like cognitive function and blood glucose control, need further exploration.