Ketones are small, water-soluble molecules your liver produces from fat when glucose is in short supply. Your body makes three of them: beta-hydroxybutyrate, acetoacetate, and acetone. They serve as an alternative fuel source for nearly every tissue in your body, including the brain, and they rise to prominence during fasting, prolonged exercise, very low-carbohydrate diets, or uncontrolled diabetes. But the story of why ketones matter goes well beyond backup energy. Over the past two decades, researchers have found that ketones also act as signaling molecules that influence inflammation, gene expression, and even how neurons fire.
How Your Body Makes Ketones
Under normal circumstances, your cells run primarily on glucose derived from the carbohydrates you eat. When you stop eating or dramatically cut carbs, insulin drops and a hormone called glucagon rises, prompting the liver to break down its stored glycogen into glucose. A typical person carries roughly 450 grams of glycogen, enough to fuel the body for about 24 hours.1PubMed Central. Long-Term Fasting-Induced Ketosis in 1610 Subjects: Metabolic Regulation and Safety Once those stores run out, the body pivots to breaking down fat. Fatty acids flood the bloodstream to fuel most cells directly, but the liver converts a portion of them into ketone bodies that can travel through the blood to reach tissues that cannot easily burn fat on their own.
This metabolic switch is a core adaptation to fasting. The liver ramps up fatty acid oxidation and ketone production in a coordinated response that researchers describe as one of the most substantial metabolic shifts the organ undergoes.2Trends in Endocrinology & Metabolism. Hepatic Adaptations to Fasting In prolonged starvation, total ketone production can climb to around 150 grams per day, with the body oxidizing the vast majority of what it produces.3JCI Insight. Ketone-body production and oxidation in fasting obese humans That is a remarkable throughput for molecules most people never think about.
A ketogenic diet triggers the same basic process without full fasting. Because insulin suppresses ketone production, the diet must keep carbohydrates very low. In practice, that means fewer than about 20 to 50 grams of carbs per day, which is roughly a single banana and a slice of bread.4PubMed Central. The ketogenic diet is not for everyone: contraindications, side effects, and drug interactions Eat much more than that and insulin rises enough to shut down ketogenesis before it really gets started.
The Brain’s Backup Fuel
Your brain is an energy hog, consuming roughly a fifth of your resting metabolic output. Under normal conditions it relies almost entirely on glucose. But the brain cannot burn fatty acids directly because they do not cross the blood-brain barrier efficiently. This creates a problem during fasting: the rest of the body can switch to fat, but the brain is stuck. Ketones solve that problem. They are water-soluble, cross the blood-brain barrier easily, and the brain’s uptake of them appears to scale with their concentration in the blood.5PubMed Central. Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases During extended fasting, ketones can supply the majority of the brain’s energy needs.
This is not just a curiosity of starvation physiology. The brain’s ability to switch fuels has attracted serious research attention in the context of neurodegenerative diseases. In Alzheimer’s disease, for instance, the brain’s ability to use glucose deteriorates years before symptoms appear. Yet brain cells retain the ability to use ketones efficiently, which has led researchers to explore whether supplying extra ketones could compensate for the glucose deficit.6PubMed Central. Brain glucose and ketone utilization in brain aging and neurodegenerative diseases Brain imaging studies support the idea that ketones can boost brain energy metabolism, and a handful of clinical studies have reported modest cognitive improvements in patients with or at risk of Alzheimer’s disease after ketogenic interventions.5PubMed Central. Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases Similar, though smaller, hints of benefit have appeared in Parkinson’s disease research. The evidence here is still early, but the biological rationale is solid enough that research groups around the world are testing ketone-based interventions ranging from ketogenic diets to oral ketone supplements.7PubMed. Ketones: potential to achieve brain energy rescue and sustain cognitive health during ageing
Ketones as Signaling Molecules
For a long time, scientists thought of ketones purely as fuel. That view has changed substantially. Beta-hydroxybutyrate, the most abundant of the three ketone bodies, turns out to be an active signaling molecule that affects how genes are read and expressed. In 2013, researchers demonstrated that beta-hydroxybutyrate directly inhibits certain enzymes involved in gene regulation, leading to increased expression of genes that protect cells against oxidative stress.8PubMed Central. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor Fasting and calorie restriction, both of which raise beta-hydroxybutyrate levels, produced the same effect in mouse tissues.
This gene-regulating ability extends to practical outcomes. In fasting mice, beta-hydroxybutyrate enhanced the expression of a glucose transporter gene in brain cells, essentially helping the brain pull in more glucose even as blood glucose was dropping.9PubMed. Epigenetic regulation of the glucose transporter gene Slc2a1 by β-hydroxybutyrate underlies preferential glucose supply to the brain of fasted mice So ketones do not just substitute for glucose in the brain; they also help the brain grab what little glucose remains. That is a surprisingly elegant two-pronged survival mechanism.
Beta-hydroxybutyrate also acts as an anti-inflammatory signal. It blocks a specific inflammatory pathway called the NLRP3 inflammasome, which is involved in a wide range of conditions from gout to metabolic syndrome. In lab experiments, beta-hydroxybutyrate suppressed NLRP3 activation triggered by urate crystals (the culprits in gout), cellular stress signals, and toxic fatty acids.10PubMed Central. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease Animal studies have followed up on this: in rats with osteoarthritis, a ketogenic diet significantly reduced NLRP3 inflammasome activity and lowered levels of inflammatory markers while also reducing cartilage and bone damage.11PubMed Central. Ketogenic diet ameliorates inflammation by inhibiting the NLRP3 inflammasome in osteoarthritis Whether these anti-inflammatory effects hold up in large human trials remains to be seen, but the mechanistic picture is consistent and growing.
Ketosis Versus Ketoacidosis
One of the most common sources of confusion around ketones is the difference between nutritional ketosis and diabetic ketoacidosis. They sound similar and both involve elevated ketones, but they are fundamentally different conditions.
In nutritional ketosis, whether from fasting or a ketogenic diet, blood ketone levels rise modestly, typically to somewhere between 0.5 and 3 millimoles per liter. Insulin remains low but present, and that residual insulin acts as a brake, preventing ketone production from spiraling out of control. Blood pH stays within a normal, safe range.
Diabetic ketoacidosis is a medical emergency. It occurs most often in people with type 1 diabetes whose bodies produce little or no insulin. Without insulin’s braking effect, ketone production runs unchecked and blood levels can exceed 20 millimoles per liter. Because two of the three ketone bodies are acids, this flood overwhelms the blood’s buffering capacity and drives pH dangerously low. The resulting acidosis can damage organs and, without treatment, can be fatal. Ketone bodies are not always protective; in the context of ketoacidosis, they become toxic to the brain and other tissues.12PubMed Central. Ketogenic diet versus ketoacidosis: what determines the influence of ketone bodies on neurons? The exact threshold at which ketones shift from helpful to harmful is an active area of investigation.
For a healthy person fasting or eating a ketogenic diet, ketoacidosis is extremely unlikely. The danger is real for people with type 1 diabetes, those with advanced type 2 diabetes who produce very little insulin, and people with severe alcohol dependence. If you have any of those conditions, monitoring ketone levels and working with a physician before attempting a ketogenic diet is non-negotiable.
The Epilepsy Connection
The ketogenic diet was not invented by wellness influencers. It was developed in the 1920s by physicians looking for a way to treat epilepsy, inspired by the ancient observation that fasting could reduce seizures, a practice documented as far back as 500 BC.13PubMed. History of the ketogenic diet The diet was widely used for two decades before being eclipsed by modern anti-seizure medications. It fell into near-obscurity, available at only a handful of children’s hospitals, until a resurgence of interest beginning in the 1990s brought it back into mainstream neurology.
Recent research has started to explain why it works. In mice, beta-hydroxybutyrate produced by a ketogenic diet increased levels of GABA, the brain’s primary inhibitory neurotransmitter, while also raising the ratio of GABA to glutamate, the main excitatory neurotransmitter. The net effect was reduced neural excitability and suppressed seizure activity. Giving beta-hydroxybutyrate on its own, without the full ketogenic diet, reproduced the anti-seizure effect.14PubMed Central. Ketogenic diet-produced β-hydroxybutyric acid accumulates brain GABA and increases GABA/glutamate ratio to inhibit epilepsy This finding is significant because it suggests the key active ingredient is a specific ketone body, not the broader metabolic state of the diet as a whole. That distinction could eventually lead to more targeted therapies that deliver the seizure protection without requiring the strict and often difficult dietary regimen.
Exercise Performance and Exogenous Ketone Supplements
The idea that ketones could improve athletic performance has generated enormous commercial interest. The logic seemed straightforward: if ketones are an efficient fuel and can spare glycogen stores during exercise, athletes who supplement with them should be able to go harder for longer. Early lab studies supported this possibility, showing that ketones could improve energetic efficiency in muscle compared to glucose oxidation alone.15PubMed. Defining ketone supplementation: the evolving evidence for postexercise ketone supplementation to improve recovery and adaptation to exercise
The real-world results have been disappointing. In a controlled cycling study, athletes who ingested ketone esters during a simulated race showed no glycogen sparing and no improvement in power output or time-to-exhaustion compared to a control group.16PubMed Central. Exogenous ketosis impacts neither performance nor muscle glycogen breakdown in prolonged endurance exercise Broader reviews of the literature have reached a similar conclusion: ketone supplements generally do not improve performance, at least not under conditions relevant to most athletes.15PubMed. Defining ketone supplementation: the evolving evidence for postexercise ketone supplementation to improve recovery and adaptation to exercise
Where exogenous ketones may have more promise is in recovery after exercise rather than during it. Researchers are now investigating whether taking ketone supplements after training sessions can accelerate glycogen replenishment, reduce muscle damage markers, or improve adaptation over time. The evidence is still preliminary, but this pivot from “fuel during exercise” to “recovery tool after exercise” represents the direction most of the serious research is heading.
On a practical level, exogenous ketone supplements come in two main forms: ketone esters and ketone salts. In a pilot study, both raised blood beta-hydroxybutyrate levels to around 1 to 2.4 millimoles per liter within 15 to 30 minutes, with levels returning to baseline by two hours.17PubMed Central. Tolerability and Acceptability of an Exogenous Ketone Monoester and Ketone Monoester/Salt Formulation in Humans Ketone esters tend to raise levels faster and higher but taste notoriously bad. Ketone salts are more palatable but deliver ketones bound to sodium, potassium, or other minerals, which can cause gastrointestinal discomfort at higher doses.
Ketones and the Heart
The heart is the most metabolically active organ in your body and is remarkably flexible about what it burns. Under normal conditions it relies heavily on fatty acids, but it readily uses glucose, lactate, and ketones as well. When ketone levels rise, the heart increases its ketone oxidation substantially, and at high concentrations ketones can become the heart’s dominant fuel source.18PubMed Central. Ketones can become the major fuel source for the heart but do not increase cardiac efficiency
There is an important caveat, though. While the heart will eagerly burn ketones, doing so does not actually make the heart work more efficiently. Research in animal models showed that the surge of energy production from ketone oxidation was not matched by a corresponding increase in cardiac work output, meaning some of that energy was essentially wasted. Cardiac efficiency actually decreased at higher ketone concentrations.18PubMed Central. Ketones can become the major fuel source for the heart but do not increase cardiac efficiency This does not mean ketones are bad for the heart, but it does push back against the notion, popular in some wellness communities, that ketones are a “superfuel” for every organ. The heart runs on them just fine during fasting or a ketogenic diet, but it is not getting a performance upgrade by doing so.
How Ketones Are Measured
If you are fasting, following a ketogenic diet, or managing diabetes, you might want to know your ketone levels. There are three main ways to check:
- Blood meters: A finger-prick device measures beta-hydroxybutyrate directly. This is the gold standard for accuracy and what clinicians use. Levels below 0.6 millimoles per liter are considered normal; 0.6 to 1.5 is light nutritional ketosis; 1.5 to 3.0 is moderate ketosis; and anything above 3.0 warrants medical attention if you have diabetes.
- Urine strips: These detect acetoacetate excreted by the kidneys. They are cheap and widely available but become less reliable over time because the body gets better at using ketones rather than excreting them. Someone well-adapted to a ketogenic diet can be in solid ketosis while the urine strip reads negative.
- Breath analyzers: These measure acetone, the ketone body expelled through the lungs. A study in adults with type 1 diabetes found a significant association between breath acetone and blood ketone levels, with the breath device showing high sensitivity (about 95%) for detecting ketosis, though specificity was more modest at around 54%.19PubMed. Accuracy of a breath ketone analyzer to detect ketosis in adults and children with type 1 diabetes In other words, if the breath device says you are not in ketosis, you probably are not; but if it says you are, a blood check is worth doing to confirm. The same study found no significant association in children, so breath analyzers may not be reliable across all ages.
For most people experimenting with fasting or a low-carb diet, a blood meter offers the clearest picture. For people with diabetes using ketone monitoring as a safety check, the blood meter is really the only option worth relying on for clinical decisions.
Long-Term Safety and Open Questions
Short-term elevations in ketones from fasting or a ketogenic diet appear to be well tolerated. A 24-week study in obese patients on a ketogenic diet found significant reductions in body weight, triglycerides, LDL cholesterol, and blood glucose, along with increases in HDL cholesterol. Kidney and liver function markers remained unchanged, and the researchers concluded no significant side effects emerged over that period.20PubMed Central. Long-term effects of a ketogenic diet in obese patients
Animal studies paint a more complicated picture when the timeframe extends further. Mice kept on a ketogenic diet long-term stayed lean but developed elevated blood lipids, fatty liver, and severe glucose intolerance driven by impaired insulin secretion. Examination of their pancreatic islet cells revealed signs of cellular stress and disrupted protein trafficking, suggesting the machinery that packages and releases insulin was breaking down.21PubMed Central. A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice A separate rat study found that long-term ketogenic feeding led to mild metabolic acidosis, lower red blood cell counts, and reduced antioxidant defenses, though liver and kidney function remained normal.22PubMed Central. Long-Term Ketogenic Diet Induces Metabolic Acidosis, Anemia, and Oxidative Stress in Healthy Wistar Rats
Translating rodent findings to humans requires caution. Mice have much higher metabolic rates, and the composition of a “ketogenic diet” in a rodent study often looks nothing like what a human would eat. Still, these results suggest that ketosis as a permanent metabolic state, rather than an intermittent one, may carry risks that a few months of human data would not reveal. The tension between promising short-to-medium-term results in people and worrying long-term results in animals is one of the biggest unresolved questions in the field.
Ketones in Cancer Research
Cancer cells are notorious for their heavy dependence on glucose, a phenomenon known as the Warburg effect. This observation has fueled interest in whether shifting the body’s fuel supply from glucose to ketones could starve tumors or at least make them more vulnerable to treatment. Research into ketone body metabolism in tumors is exploring several angles: ketones as signaling mediators that affect how cancer cells behave, their influence on inflammation and oxidative stress within tumors, and whether a ketogenic diet could make standard therapies like chemotherapy and radiation more effective.23PubMed Central. Comprehensive Overview of Ketone Bodies in Cancer Metabolism: Mechanisms and Application
The reality is messier than the headline version. Some cancer types can actually use ketones as fuel, and in certain contexts ketone bodies may even promote tumor growth. The research is at an early mechanistic stage, mostly in cell cultures and animal models, and no large-scale clinical trials have established ketogenic diets as a standalone cancer treatment. What does seem increasingly plausible is that ketogenic interventions might serve as an adjunct, making existing treatments work better in specific cancers. Anyone considering a dietary intervention alongside cancer treatment should do so under medical supervision, because malnutrition and muscle wasting are already serious risks during cancer care.
Why Humans Evolved to Run on Ketones
Ketone metabolism is not a biochemical accident. It appears to be deeply woven into human evolution, particularly because of our unusually large brains. Throughout human history, food supplies were unpredictable, and the ability to keep the brain fueled during famine was a survival advantage.24PubMed Central. Brain Ketone Bodies in Health, Evolution and Disease
Human infants offer a striking illustration. Newborn babies carry an unusually high proportion of body fat for a terrestrial animal, and both their brains and their fat stores each account for roughly 11 to 14 percent of body weight. That fat serves triple duty: it provides a large reserve of fatty acids for general energy, it supplies the precursors for ketone bodies that the developing brain uses for building its lipid-rich structures, and it stores long-chain polyunsaturated fatty acids critical for normal brain development.25PubMed. Survival of the fattest: fat babies were the key to evolution of the large human brain In other words, the fatness of human babies is not a quirk; it is an evolutionary strategy for building and protecting a disproportionately large brain, with ketone metabolism as the metabolic bridge.
This evolutionary lens helps explain why ketone metabolism is so sophisticated. It is not a crude emergency backup but a finely tuned system with its own signaling pathways, gene-regulatory functions, and anti-inflammatory properties. The body did not evolve these features for people trying to lose weight in the twenty-first century. It evolved them because, for most of human history, the ability to switch metabolic fuels seamlessly was the difference between surviving a lean season and not.