Ketone Bodies as Fuels, Signals, and Redox Modulators

Ketone bodies (acetoacetate, AcAc, and β-hydroxybutyrate, βOHB) have traditionally been regarded as alternative energy substrates produced when the glucagon-to-insulin ratio rises, as occurs during fasting, time-restricted eating, carbohydrate restriction, ketogenic diets, and endurance exercise. Growing evidence indicates that their functions extend beyond fuel provision. This review brings these functions together and assesses the strength of the evidence supporting each of them. We organize the evidence along three axes: ketone bodies as oxidative fuels, as receptor and epigenetic signals, and as modulators of redox homeostasis. As fuels, hepatic ketogenesis converts adipose-derived lipid carbon into water-soluble substrates that reach tissues that cannot oxidize long-chain fatty acids, with the mitochondrial isoform of HMG-CoA synthase (HMGCS2) controlling production and SCOT/OXCT1 controlling utilization. As a signaling molecule, βOHB engages HCAR2, inhibits class I and IIa histone deacetylases, suppresses NLRP3 inflammasome activation, and donates the acyl group for histone lysine β-hydroxybutyrylation. The strength of the supporting evidence is uneven across these mechanisms, and we indicate for each one the experimental system, the concentration range, and whether the effect has been shown for βOHB, for AcAc, or for both. As redox modulators, ketone oxidation reduces the mitochondrial NAD+/NADH couple while oxidizing the coenzyme Q pool, and βOHB-dependent HDAC inhibition and Nrf2 activation induce FOXO3A, catalase, MnSOD, NQO1, and glutathione synthesis. We argue that this response is best described as hormetic and context-dependent rather than as a universal antioxidant effect, since a transient pro-oxidant signal appears to initiate the defense program and AcAc behaves as a pro-oxidant at supraphysiological concentrations. A recurrent difficulty in the field is that fasting, caloric restriction, and exercise also engage most of the pathways involved, independent of ketone bodies, and that human redox data from endogenous physiological ketosis remain scarce. We therefore propose a shortlist of measurable human endpoints, including Nrf2 and FOXO target genes, SOD and catalase activity, and the GSH/GSSG ratio, to test the ketone-specific component of these effects.