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Ketones are water-soluble molecules synthesised by the liver from fatty acids when carbohydrate availability is low, whether through fasting, dietary carbohydrate restriction, or prolonged exercise. The predominant form, beta-hydroxybutyrate (BHB), crosses the blood-brain barrier via monocarboxylic acid transporters and is oxidised in neuronal mitochondria to generate ATP, providing an alternative oxidative substrate to glucose.
BHB also acts as a signalling molecule, inhibiting histone deacetylases and modulating gene expression beyond its role as fuel.
How it works
The liver produces ketone bodies through ketogenesis, triggered when low carbohydrate availability drives fatty acid oxidation beyond the processing capacity of the tricarboxylic acid cycle. As acetyl-CoA accumulates, the liver diverts the excess into three ketone bodies: beta-hydroxybutyrate (BHB), acetoacetate, and acetone.2 BHB is the quantitatively dominant form in circulation and the primary substrate that peripheral tissues, including the brain, extract and oxidise.
BHB crosses the blood-brain barrier through monocarboxylic acid transporters (MCT1 and MCT2) and enters neuronal mitochondria, where it is converted to acetyl-CoA for ATP synthesis. This oxidative pathway also shifts the mitochondrial redox balance to reduce the production of reactive oxygen species relative to glucose oxidation.2 Cerebral catheterisation studies of patients fasted for five to six weeks showed ketone bodies supplying approximately two-thirds of the brain's energy requirements, a ceiling glucose alone cannot sustain across extended food deprivation.1 That proportion applies to extreme starvation; in nutritional ketosis of days to weeks, glucose and ketones share the load.
Beyond serving as fuel, BHB functions as a signalling metabolite. It inhibits class I and IIa histone deacetylases and activates cell-surface receptors GPR41 and GPR109A, directly influencing gene expression, inflammatory signalling, and neuronal excitability.3 This signalling dimension underlies research into ketogenic therapies for drug-resistant epilepsy and age-related neurodegeneration, where the metabolic and anti-inflammatory properties of BHB may confer benefits that extend beyond simple caloric provision.
Example
An endurance athlete midway through a multi-hour effort has exhausted much of his available muscle glycogen. Rather than slowing to preserve what little remains, his liver has elevated circulating BHB, which working muscles and the brain are now oxidising alongside residual glucose. His pace is maintained not because he has more fuel, but because he has switched to a supplementary oxidative substrate that his physiology produces on demand.
Ketones do not replace glucose in metabolically healthy subjects; they extend the fuel range when glucose becomes the limiting resource.
Why it matters
The practical significance of ketones divides across two populations. For people with impaired glucose metabolism, whether from insulin resistance, age-related metabolic decline, or mild cognitive impairment, the available evidence is more promising. A 2026 meta-analysis of 18 trials found exogenous ketone administration produced a statistically significant improvement in cognitive performance (SMD 0.26),4 with effects that did not differ substantially by population type or supplementation form. The most established clinical application is drug-resistant paediatric epilepsy, where ketogenic dietary therapy has decades of controlled evidence.3
For metabolically healthy adults with normal glucose regulation, the picture is more qualified. Controlled trials of sustained nutritional ketosis have not consistently produced measurable cognitive gains, suggesting the brain's fuel-switching machinery confers less marginal benefit when its primary fuel supply is already abundant.4 Where ketones become more compelling for healthy performers is during prolonged physical exertion, when glycogen depletion makes supplementary oxidative substrates practically relevant.
What is the difference between ketosis and diabetic ketoacidosis?+
Nutritional ketosis is a controlled, regulated state in which circulating BHB rises to 0.5-3 mmol/L in response to carbohydrate restriction or fasting. Diabetic ketoacidosis is a medical emergency in which BHB exceeds 10-25 mmol/L due to absent insulin, producing severe acidosis. The concentrations and clinical contexts are entirely distinct.{{cite:10.1016/j.cmet.2016.12.022}}
How do ketones affect brain performance and cognition?+
A 2026 meta-analysis of 18 trials found exogenous ketone supplementation produced a modest but significant improvement in cognitive performance (SMD 0.26) across healthy adults and those with mild cognitive impairment or Alzheimer's disease.{{cite:10.3389/fnut.2026.1802531}} Benefits appear more pronounced in people with compromised glucose metabolism; healthy adults with normal glucose regulation show attenuated or absent gains in controlled trials.
How long does it take to enter nutritional ketosis?+
Under strict carbohydrate restriction (typically below 20-50 g per day), hepatic glycogen is depleted within 12-48 hours, after which the liver upregulates ketogenesis and blood BHB rises above 0.5 mmol/L. Full metabolic adaptation, including efficient peripheral ketone utilisation, may take two to four weeks.{{cite:10.1016/j.cmet.2016.12.022}}
Can exogenous ketone supplements replace a ketogenic diet?+
Exogenous ketones (typically salts or esters) raise circulating BHB acutely but do not reproduce the full metabolic state of nutritional ketosis, which involves sustained low insulin, elevated fatty acid oxidation, and adaptation of peripheral enzymes.{{cite:10.1146/annurev-nutr-071816-064916}} Current evidence does not support supplements as a dietary substitute; they are more accurately described as a short-term substrate addition.
