Ketosis

Ketosis is a metabolic state in which the body relies on ketone bodies for energy due to low glycogen levels in the liver. Ketone bodies are produced by the breakdown of fatty acids. Ketosis results from the utilization of body fat as an energy source.

Ketone bodies

Ketonuria

Ketone bodies synthesis

Diet

Ketosis occurs when the body lacks sufficient carbohydrates to replenish glycogen in the liver. An example of a diet that induces ketosis is the Atkins diet, which initially limits carbohydrate intake to less than 20g per day. It takes approximately 48 hours for the brain to transition from using glucose to ketone bodies for energy. Ketosis helps prevent the body from using protein, found in muscles, for gluconeogenesis to produce glucose.

Ketosis and the Brain

A ketogenic diet essentially mimics starvation, causing the body to enter a metabolic state known as ketosis. Human bodies typically rely on carbohydrates for energy: ingested carbohydrates are broken down into glucose, which is primarily transported and used as energy or stored as glycogen in liver and muscle tissue. When dietary carbohydrates are scarce (usually below 50g/day), the liver becomes the sole provider of glucose for the body, particularly for the brain, which accounts for ~20% of total energy expenditure. The brain cannot directly use fat for energy. Once liver glycogen is depleted, ketone bodies derived primarily from dietary or body fat serve as an alternative energy source to maintain normal brain cell metabolism. The liver produces ketones – ?-hydroxybutyrate (BHB), acetoacetate, and acetone – which are released into the bloodstream, taken up by the brain and other organs, shuttled into the mitochondria, and used as fuel.

Brain Protection Mechanisms

Ketosis may protect the brain against various neurological diseases through several mechanisms. One possible explanation is energy: many neurological diseases share a common problem of deficient energy production. Ketones, particularly BHB, may provide more efficient fuel than glucose, offering more energy per unit of oxygen used. A ketogenic diet also increases the number of mitochondria in brain cells.

Ketones directly inhibit the production of reactive oxygen species, which are highly reactive molecules that can damage cellular structures, and increase the activity of glutathione peroxidase, an innate antioxidant system. A ketogenic diet also reduces inflammation by increasing poly-unsaturated fatty acids (PUFAs) such as DHA and EPA, which inhibit the expression of genes encoding for pro-inflammatory factors.

Ketosis may also protect against excitotoxicity, a condition in which over-excited neurons die. Ketones have been shown to directly inhibit the release of the excitatory neurotransmitter glutamate, thereby decreasing excitatory transmission. In addition, ketones increase the inhibitory neurotransmitter GABA, which may provide both anti-seizure effects and neuroprotection.

Evidence of Ketosis as a Neuroprotector

Several studies suggest that a ketogenic diet may be protective against brain injury and have positive effects on cognitive function:

A study involving 23 elderly individuals with mild cognitive impairment demonstrated that a ketogenic diet improved verbal memory performance after six weeks compared to a standard high-carbohydrate diet. In a double-blind, placebo-controlled study involving 152 patients with mild to moderate Alzheimer's disease, participants were given either a ketogenic agent or a placebo while maintaining a normal diet. After 90 days, those receiving the drug showed significant cognitive improvement compared to the placebo group, with improvement correlating to blood ketone levels. A pilot study with seven patients with Parkinson's disease found that five participants who adhered to the diet for 28 days experienced a marked reduction in their physical symptoms. An animal model study of Amyotrophic Lateral Sclerosis (ALS) found that a ketogenic diet delayed motor neuron death and led to histological and functional improvements, although it did not increase lifespan. Clinical trials are currently underway. Despite the potential neuroprotective benefits, a long-term ketogenic diet may be associated with some side effects:

Common complaints include constipation, dehydration, and electrolyte and micronutrient deficiencies. More serious complications can include an increased risk of kidney stones, gallbladder problems, and bone fractures, especially in children. Menstrual irregularities are often observed in women, potentially impacting fertility. Historically, ketoacidosis (blood acidification due to pathological levels of ketones) was proposed as a side effect; however, nutritional ketosis cannot achieve the ketone levels required to induce this life-threatening state. While there are no studies directly monitoring the side effects of ketosis, it is too early to conclude that the diet is completely safe for everyone.

Further Research

More research is needed to fully understand the mechanisms underlying the neuroprotective effects of ketosis. Some hypotheses suggest that the acidity of ketones may play a role in the positive effects of a ketogenic diet on Type II Bipolar disorder, and that global changes due to calorie restriction and regulation of the satiety hormone Leptin may alter brain function.