You’ve undoubtedly heard the buzzwords: ketogenic diet, intermittent fasting. I don’t have much of an opinion about what that all does for your waistline, but I venture to say that ketones may benefit your brain.

Some doctors have recommended, with rock-solid evidence, diets that increase brain ketone levels as part of the regimen to treat drug-resistant epilepsy in children. Others claim that high ketone levels are like a magic bullet and may benefit those suffering from a wide variety of neurological disorders, including headache, neurodegenerative diseases, sleep disorders, bipolar disorder, autism, and even brain cancer. Researchers reported that ketogenic diets may improve memory performance, verbal skills, and processing of thoughts in cognitively impaired individuals, such as those with Alzheimer’s disease. Improvements in memory, language, and problem-solving have also been reported in non-demented elderly individuals and those with Parkinson’s disease.

In order for your body to generate ketones for your brain, you must enter the physiological state of ketosis.

What’s ketosis?

When you eat three square meals a day and fill your plate with representatives of each of the four food groups, your brain burns sugar, specifically glucose, and boatloads of it. That’s all well and good because your brain runs on heavy fuel, vacuuming up two out of every ten calories you consume. If you’re swaying in the hammock under a shady tree and contemplating life’s mysteries or having a vivid daydream, that percentage may rise to an even fifty.

When your blood sugar dips, your ever-voracious brain commands your body to produce an alternative energy source—ketones—and you enter a state of ketosis. Two common situations where people intentionally induce swooning sugar levels are intermittent fasting or a ketogenic diet.

Intermittent fasting is picking twelve or sixteen hours a day to not eat. After 12 hours without food, many people deplete their glycogen (sugar energy stored in the liver). In the absence of sugar, certain organs in your body turn to another fat-based energy source: ketones. A ketogenic diet, low in carbs, adequate in protein, and high in fat, accomplishes the same ends without self-induced starvation. There are two mechanisms by which ketones may benefit your brain: metabolic switching and neuronal (brain cell) shielding.

Metabolic switching

Intermittent fasting is a mild metabolic stressor. Under ordinary circumstances, the brain runs on glucose (sugar), which it burns differently than ketones (derived from ketogenic amino acids and fatty acids). Some scientists have reported that metabolic switching between the two different types of fuel may optimize brain function and resilience. Researchers surmise that metabolic switching impacts multiple signaling pathways that promote neuroplasticity (the ability of neurons to change structure and function). Metabolic switching may also increase the resistance of the brain to injury and disease. In 2020, scientists from Singapore reported that intermittent fasting led to increased growth and reproduction of nerve cells (neurons) in the hippocampi (the area of the brain associated with memory formation) of adult rats.

Metabolic switching may confer particular benefits on the neuronal circuits involved in cognition and mood. In 2018, scientists at Johns Hopkins reported their findings on the effects of fasting on the brain. They intermittently deprived rats of food for stretches of either sixteen or twenty-four hours. They discovered that the metabolic brain pathways switched back and forth in the test animals. During the fasting state, the animals’ brains metabolized ketones, and during the recovery period, their brains reverted to sugar metabolism. They reported that intermittent metabolic switching, repeating cycles of a metabolic challenge, optimized brain function and resilience throughout the rats’ lifespan. They reported particular benefits on the neuronal circuits involved in problem-solving and depression.

Neuronal shielding

Independently of metabolic switching, ketones themselves have powerful antioxidant properties. They decrease the production of oxidizing molecules (which might otherwise damage cellular proteins or DNA) and enhance their breakdown. Ketones reduce brain inflammation by increasing the brain availability of certain polyunsaturated fatty acids. Higher levels of ketones increase the number of mitochondria, so-called “energy factories” in brain cells. A recent study found that ketones enhanced mitochondrial activity in the hippocampus, a part of the brain important for learning and memory.

Ketones trigger the release of a brain molecule called BDNF (brain-derived neurotrophic factor), a molecule that helps neurons (brain and nerve cells) in several ways:

• BDNF has been found to be essential in allowing neurons to thrive, grow, and mature.
• BDNF improves the survival of brain and nerve tissue that has been subjected to injuries (healing the brain from stroke or trauma).
• BDNF has been demonstrated to improve the function of the hippocampus (part of the brain responsible for memory formation) and basal forebrain (part of the brain that promotes and facilitates learning).
• BDNF encourages growth and differentiation of new neurons (nerve cells) and synapses (areas where nerves join).
• BDNF enhances the survival of neurons subjected to certain degenerative diseases. In Parkinson’s disease (PD), BDNF enhances the survival of dopaminergic neurons, improves dopaminergic neurotransmission and motor performance.

Shielding from brain inflammation

Why are the anti-inflammatory effects of ketones so beneficial to the brain? In 2019, researchers from Stanford discussed their theory of the mechanism by which systemic inflammation may affect the brain. The brain has a built-in system known as the blood-brain barrier (BBB), which filters out toxins before they can reach the precious neurons. The scientists believe that long-standing systemic inflammation may burn tiny holes in the BBB. No longer able to serve as a protective barrier, the compromised BBB becomes a sieve and allows poisons to attack unimpeded.

In 2019, a multinational team of scientists reported on their findings of chronic systemic inflammation (a long-lasting inflammation that affected widespread areas of the body). They emphasized that inflammation of this type may contribute to neurodegenerative disorders such as Alzheimer’s disease (and other dementias) as well as Parkinson’s disease. Other researchers have pointed to inflammation as a contributory factor to psychological disorders, such as depression. Some of the factors that contribute to chronic systemic inflammation may be outside your control, such as exposure to environmental and industrial toxins. Other factors that lead to chronic inflammation, such as physical inactivity and poor dietary choices, are within your control. In addition to raising your ketone level, you can protect your brain from the damaging effects of chronic inflammation by avoiding excess sugar, too much alcohol, fried foods, and nitrates.

Ketones as bystander

Ketones seem to have a direct beneficial effect on neurons, brain circuitry, and certain neuronal functions. In other respects, it may be the intermittent fasting (especially when coupled with exercise) that does the trick. There’s some evidence that in the fight against Alzheimer’s disease, the ketones may just be along for the ride.

California researchers, in 2021, discovered that the Tau protein, which may be responsible for Alzheimer’s disease, is more complex than previously understood. Alzheimer’s is associated with neuronal damage, which may be caused by an intracellular buildup of plaques and tangles. It turns out that there are multiple versions of the Tau protein, and only some of them may be toxic to the brain.

The scientists also reported that the body has a self-defense mechanism against malicious Tau proteins. Defective proteins within cells may be eaten up, a process called autophagy. In certain Alzheimer’s patients, autophagy becomes defective. It turns out that intermittent fasting may improve autophagy (eating up the bad Tau proteins) because it makes the remainder of the body crave the amino acids locked up inside the Tau proteins. It also turns out that regular exercise may also boost autophagy by a similar mechanism.

Marc Arginteanu is a neurosurgeon and author of Azazel’s Public House.