Fasting has been used as a form of therapy for epilepsy throughout the history of medicine. But in 1921, Dr Woodyatt at Rush Medical College in Chicago observed that that there were a couple of ketone molecules that appeared in the blood of subjects undergoing starvation or low-carbohydrate/high-fat content diets, while Dr Wilder at the Mayo Clinic proposed that similar effects to those of fasting on epilepsy could be obtained by inducing the production of those same molecules through diet.

This was the origin of ketogenic diets, which became one of the most widely used treatments for epilepsy in children. It is still used to this day as an alternative to pharmacological treatments, although it is not known how it works.

The ketogenic diet is characterized by a continued intake of low amounts of carbohydrates, high doses of fat, and regular amounts of protein. This changes our body’s metabolism by turning fat into our main fuel: Instead of obtaining energy primarily from carbohydrates, our body obtains energy from stored fat and becomes more efficient at using fat as the main energy source. Although the intake of fat is higher, the net result is loss of stored fat.

Ketogenic low-carbohydrate/high-fat diets have been shown to be highly effective in promoting weight loss. They are called ketogenic because they lead to the production of molecules known as ketone bodies.

Ketone bodies, our brain’s other fuel

Glucose is our body’s primary source of energy. When regular amounts of carbohydrates are ingested, our carbohydrate stores keep being replenished and glucose keeps being used as fuel. But when blood glucose levels drop and carbohydrate stores are exhausted, fats stored in adipose tissue are broken down and free fatty acids are released into the blood.

Fatty acids are then taken up by cells to be used to produce energy. This happens, for example, during periods of carbohydrate restriction, fasting or starvation, or prolonged intense exercise.

However, fatty acids cannot cross the blood-brain barrier and therefore cannot be used by neurons and glia in the central nervous system. However, the liver can use acetyl-CoA obtained from fatty acid metabolism to produce ketone bodies – acetone, beta-hydroxybutyrate and acetoacetate. Ketone bodies are able to cross the blood-brain barrier and can be used as a replacement for glucose in the brain.

One of the reasons why ketogenic diets are often more effective than low-fat diets in promoting weight loss is the fact that ketone bodies may actually suppress appetite by acting on the hypothalamus, where signals from appetite-regulating hormones such as leptin or ghrelin are combined, by interacting with these hormonal signals.

Ketone bodies and brain health

The effects of ketogenic diets are not limited to seizure prevention. Ketogenic diets have shown beneficial effects and are being studied as therapeutic options for an impressively high range of neurological disorders: cognitive impairment, migraine, pain, traumatic brain injury, stroke, Alzheimer’s disease, Parkinson’s disease, sleep disorders, autism, amyotrophic lateral sclerosis and multiple sclerosis, for example.

This effect may be due to a neuroprotective action of ketone bodies. Although the mechanisms are poorly understood, studies in animal and cellular models have shown that ketone bodies can protect neuronal and glial cells against different types of cellular injury and even death. It is believed that this effect may be due to increased energy production and energy storage, since ketone bodies are actually more effective energy sources for neurons. This may arm neurons with an improved ability to resist metabolic insults.

Importantly, ketone bodies can have antioxidant and anti-inflammatory effects. Oxidation and inflammation are the main motors of aging and of a number of pathologies, particularly neurodegenerative diseases. By reducing oxidative stress and chronic inflammation, ketogenic diets can delay aging and delay or even decrease the development of many of the diseases mentioned above.

Furthermore, ketogenic diets are effective routes to weight loss, as already mentioned; since obesity has been associated with – for example, accelerated cognitive decline and increased risk of dementia, Alzheimer’s disease and stroke – weight loss by itself can bring great benefits to brain health.

Another important therapeutic action of ketogenic diets may be an anti-cancer effect. Cancer cells have high metabolic rates that allow their fast proliferation. It is possible that depriving these cells from glucose, the fuel they grew on, may hamper their growth. Research has shown that animals with brain tumors that are placed on a ketogenic diet show a marked decrease in the rate of tumor growth, most likely due to the lack of glucose. There are even case reports of humans with brain tumors who have greatly improved due to the adoption of a ketogenic diet.

But besides the neurological effects of ketogenic diets, there are many other health benefits described for a ketone-based metabolism. Ketogenic diets can decrease both plasma glucose and insulin concentrations, decreasing the likelihood of developing type 2 diabetes and other metabolic diseases; the levels of blood triglycerides can also be diminished, LDL cholesterol can be reduced and HDL cholesterol can be increased, thereby also decreasing the risk of cardiovascular diseases.

It is arguable that evolution hasn’t prepared us for the amount of carbs we ingest. Maybe we would be better off running on ketone bodies.

References

Barañano, K. W., & Hartman, A. L. (2008). The ketogenic diet: Uses in epilepsy and other neurologic illnesses. Current Treatment Options in Neurology, 10(6), 410–419. doi:10.1007/s11940-008-0043-8

Gano, L. B., Patel, M., & Rho, J. M. (2014). Ketogenic diets, mitochondria, and neurological diseases. The Journal of Lipid Research, 55(11), 2211–2228. doi:10.1194/jlr.r048975
Gasior, M., Rogawski, M. A., & Hartman, A. L. (2006). Neuroprotective and disease-modifying effects of the ketogenic diet. Behavioural Pharmacology, 17(5-6), 431–439. doi:10.1097/00008877-200609000-00009

Gibson, A. A., Seimon, R. V., Lee, C. M. Y., Ayre, J., Franklin, J., Markovic, T. P., … Sainsbury, A. (2014). Do ketogenic diets really suppress appetite? A systematic review and meta-analysis. Obesity Reviews, 16(1), 64–76. doi:10.1111/obr.12230

Kinzig, K. P., Honors, M. A., & Hargrave, S. L. (2010). Insulin sensitivity and glucose tolerance are altered by maintenance on a Ketogenic diet. Endocrinology, 151(7), 3105–3114. doi:10.1210/en.2010-0175

Klein, P., Tyrlikova, I., & Mathews, G. C. (2014). Dietary treatment in adults with refractory epilepsy: A review. Neurology, 83(21), 1978–1985. doi:10.1212/wnl.0000000000001004

Seyfried, T. N., Marsh, J., Shelton, L. M., Huysentruyt, L. C., & Mukherjee, P. (2012). Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer? Epilepsy Research, 100(3), 310–326. doi:10.1016/j.eplepsyres.2011.06.017

Stafstrom, C. E., & Rho, J. M. (2012). The Ketogenic diet as a treatment paradigm for diverse neurological disorders. Frontiers in Pharmacology, 3. doi:10.3389/fphar.2012.00059

Wheless, J. W. (2008). History of the ketogenic diet. Epilepsia, 49, 3–5. doi:10.1111/j.1528-1167.2008.01821.x

Image via Ann_San / Pixabay.