Researchers have found that a ketogenic diet, or exogenously supplied ketones, will situate your brain in a rejuvenated state.

If your head is cut off from your body and sewn onto a different body, have you undergone a head transplant or a body transplant? Most of us agree that we, our I, our most immediate selves, are not our bodies. We are relegated to our head, more specifically our brain, and consist of a model of reality produced by a vast population of neurons. Yes, we are a model of the world, and a part of that model is our self.

If you cut off your hands (since we’re already lopping of body parts) you cannot anymore grip things, you are left handicapped. Similarly, if you cut out a part of your cortex you are “corticapped” and can no longer experience what was represented in that specific part of your brain.

Delimited parts of your cerebral cortex, the outer layer of your brain, receive and represent very specific sensory inputs, such as the touch on certain body parts, or shapes in distinct part of your visual field. Other areas receive this information and start integrating inputs from different senses to build a more complete and unified representation of the world. In this process, the sensory information travels up a hierarchical ladder where higher levels represent increasingly complete and integrated percepts.

Losing a part that integrates, say, your visual information with the rest of the senses may leave you with an agnosia, like the titular patient in the book “The man who mistook his wife for a hat”. When asked what the object in front of him was (a rose) he could not connect his visual impression with the rest of his cortex because of a break in the command chain. He could see the rose but he couldn’t perceive it:

‘About six inches in length,’ he commented. ‘A convoluted red form with a linear green attachment.’ ‘It lacks the simple symmetry of the Platonic solids, although it may have a higher symmetry of its own. . . . I think this could be an inflorescence or flower.’

As he later got to use a different sense, olfaction, to investigate the rose he could finally fully perceive it and tie it together with the rest of his knowledge:

‘Beautiful!’ he exclaimed ‘An early rose. What a heavenly smell!’

However, as gestalt psychology has taught us, with the delightful use of visual illusions (see below), we are not merely integrating sensory information, there is also a top-down, descending control over simpler lower level sensory representations. Higher levels of the brain tries to make sense of lower level inputs and will try to predict their causes.

The Kanizsa triangle. There seems to be a white triangle in the foreground and you can even perceive the edges of it.

If our perception was only shaped by integrating sensory inputs, there would be no phantom edges in the image above, since there is no triangle there. However, higher levels predict that there should be such edges because of the likelihood of a triangle depending on the context of the other shapes.

At the figurative “top” of the sensory hierarchy we find the hippocampus, a seahorse shaped structure the size of your little finger. It is the end (or beginning?) of the cortex where the sheet curls up into a little spiral before doubling back onto itself.

So what happens when the hippocampus is cut out? The conductor Clive Wearing who lost his hippocampi to a viral infection said, in the documentary “The Man with the 7 Second Memory“:

“I have never been conscious since I’ve been ill. I don’t know what I’ve been thinking.”

[Interviewer] ”What does being unconscious mean?”

“Same as death. No difference between day and night. No thoughts at all. Day and night the same.” “Can you imagine what it’s like to have one night, 20 years long? With no dream? That’s what it has been like. Just like death. No difference between day and night. No thoughts at all.”

It is hard to image that a person can mean this, being without thoughts and consciousness, while seeming lucid and be able to express himself. But this highlights how us with normally functioning brains cannot imagine what it is like to lack a significant part of cognition or consciousness.

Whereas Wearing’s case is exotic and rare, sadly many people go through the business of losing the function of their hippocampus and with that their context, their memories and themselves. Dementia, literally “being out of one’s mind”, affects an inordinate amount of people and the prototypical case, Alzheimer’s disease, affects one person for every minute that ticks by, in the USA alone. Typically, the first area to be affected is the hippocampus and adjoining areas leading to a loss of short term memory, context and perception, but eventually larger parts of the brain are affected, resulting in difficulties with language, motor behavior and personality changes. Sudden bursts of aggression, delusions and a loss of insight often follows and eventually the patient is completely dependent on caregivers. Death typically follows from a loss of motor control of the muscles that govern swallowing, leading to the inhalation of food and subsequent pneumonia leading to the patient passing.

Alzheimer’s disease is now the 6th leading cause of death in the US, which is more than breast and prostate cancers combined. 5.8 million Americans live with the condition, a number that is projected to grow to 14 million by 2050.

There has been practically no success in treating the disorder pharmacologically, although not because of a lack of trying. Hypotheses have mostly focused on neuroanatomical substrates that coincide with the disorder, agglomerations of pathological plaques and fibrillary tangles of the protein tau that speckle the cortex. But to no avail. The enormous potential of the market has the pharmaceutical companies going crazy to find a treatment, but so far only a handful of drugs are available, and they only provide subtle palliative amelioration of the symptoms, thus no cure and no cessation of the progression.

So what about prevention? Some cognitive lifestyle factors have been linked to a later onset of Alzheimer’s, such as reading or playing a musical instrument (1). But the most likely changes that may have an effect relates to the metabolic well being of the patient. Physical exercise and a good diet may decrease the rate of dementia and may also reduce the symptoms of the disorders (2, 3). In fact, more and more evidence point to a close relationship between Alzheimer’s disease and insulin resistance, not least shown by the strong correlation between the disease and type 2 diabetes. Up to 80% of patients with Alzheimer’s may be insulin resistant or have type 2 diabetes and some scientists even refer to the disorder as type 3 diabetes (4). Earlier it was thought that the brain doesn’t care about insulin since glucose can enter neurons using a separate pathway that doesn’t rely on the hormone. However, insulin still fills a function and is needed by the brain cells to be able to process glucose correctly. Moreover, after it was found that insulin regulates the gene expression of tau, the field has shifted its attention towards it.

Thus, it seems that as people have supranormal levels of insulin in their blood, a condition found in more than half of the US population, just as the rest of the body, the brain stops paying attention to it and becomes resistant to its effects. As neurons stop receiving insulin they also stop receiving adequate energy since their glucose metabolism is severely hampered.

As neurons cannot metabolize fat directly, when carbohydrates are scarce, the brain instead starts to rely on a different substrate called ketones. These are formed in the liver as glucose dwindles because of a lack of carbs in the diet, and are used mainly by the heart and brain. Ketones is the brain’s favorite fuel and uses it preferentially to glucose, which will always be present in the blood, even in the absence of carbohydrates in the diet. Therefore, it is possible to get into the ketogenic state even without carb-restriction by supplying the ketones as a supplement, typically as a ketone salt or ester.

The benefits of ketones is becoming increasingly evident in both the nutrition and mental health fields and confer advantages against heart disease, metabolic disorders, depression and dementia. In a randomized placebo-controlled trial of 152 patients with moderate Alzheimer’s, a ketogenic treatment approach led to significant improvement in memory, and the improvement was correlated to the blood levels of the ketones. And remember, improvements in cognitive symptoms in Alzheimer’s is exactly what has never been found with medication.

A study published on March 3 this year (5) looked at the effect of ketones on the brain and its relationship to aging. Their approach was unconventional but quite brilliant. First they looked at a large data set of previously published data from fMRI scans of almost 1000 subjects of ages ranging from 18 to 88. Using computational techniques they determined something they called network stability, defined as the brain’s ability to sustain functional communication between different regions. They showed how this network stability deteriorated with age and that it correlated with the subjects cognitive capacity. At 60 years of age, their cohort showed the largest rate of deterioration, but signs of worse network stability started already at 47 years of age. They also found that younger participants that had type 2 diabetes had an increased brain age, compared to age matched healthy controls.

Next they used a different set of subjects, twelve 21-35 year old participants were subjected to three different scenarios and scanning sessions in a randomized order. Thus, all participants went through each scenario, which is an excellent way to control for individual variability. In one scenario, the subjects ate a ketogenic diet, that is minimal carbs, moderate protein and a majority of fat for a week before the scan. In the second scenario they fasted from the evening before, and in the control scenario they ate a standard diet. What the researchers found when they scanned the participants was that the network stability was higher while in the fasted or ketogenic state. Thus, allowing the brain to use ketones as energy, a source that is not dependent on insulin, led to a younger behaving brain. To assert that the effect stemmed from the ketones the scientists did a further scan where 30 subjects were fasted but drank a drink before the scan containing either glucose or ketones. Also here did they see the effect of the brain performing as a younger person while on the ketogenic fuel.

To further probe the possibility to use ketone esters as a therapy with a normal diet, they subjected a single participant who had eaten a normal diet the day before with only glucose on one test day, and glucose plus the ketone ester on another. Also here they saw the effect of the ketones on the brains network stability, proving that it may be a feasible treatment strategy for improving the brain health of demented patients.

To summarize, the study showed that subjects who have been on a short term ketogenic diet have a more stably working brain, more similar to younger brains. The benefits depended directly on the ketones and could also be induced by exogenous ketones eaten right before the brain scan, suggesting that it is most likely the ketones in themselves that somehow produces the effect.

There are of course caveats in the study. First of all, what is network stability? As I understand it, the scientists divided a long brain scan session into 24 second long epochs and then correlated the activity between all these epochs. Network stability would thus define a brain that doesn’t do much and show less dynamics. Is this the brain you’d want? Probably, since they also showed that what they defined as network stability was negatively correlated with age, cognitive decline and with bad health in younger subjects (type 2 diabetes). But what it actually corresponds to is not at all clear and that is an important point when interpreting the study.

Moreover, just as with all the different conditions that ketogenic diets are used to treat, we have no idea why they work. It could be that they upregulate mitochondria, provide more energy to starved neurons, the ketones may block or open certain ion channels, we just don’t know. But the results are striking: anyone’s brain gets more stable by a ketogenic diet and look like a younger one. Everyone should try the ketogenic diet to feel the effects of mental clarity and evaluate what effect it has on their minds.

Best wishes

Martin Hägglund, PhD