Fig. 2

Scheme of cell-protective functions of ketone bodies. The metabolic shift towards fat oxidation and ketolysis during starvation or ketogenic diet is associated with mitochondrial stress characterized by increased levels of ROS and increased ratios of NAD⁺/NADH and AMP/ATP as well as AMP/ADP. These “danger signals” cause a protective adaptive (hormetic) cellular response, via the activation of Nrf2, SIRT1, SIRT3, and AMPK, respectively. Ketone bodies also activate ROS production from NOX4, and βOHB alters the gene expression pattern by promoting histone acetylation via inhibiting class I and II HDACs and possibly by direct β-hydroxybutyrylation of histones. Long-term consequences of the initial moderate metabolic stress include upregulation of anti-oxidative and anti-inflammatory activities and improved mitochondrial function. ROS, radical oxygen species; Nrf2, nuclear factor erythroid 2-related factor 2; SIRT, sirtuin, silent information regulator; AMPK, AMP-activated kinase; NFkB, nuclear factor kappa B; NOX, NADPH oxidase; HDAC, histone deacetylase; FOXO, forkhead box O