How Ketosis Changes Brain Fuel and Metabolic Flexibility

Steven Bartlett: When you discussed cruciferous vegetables, I was surprised to hear that they contain cancer-preventive chemicals. Research links foods such as kale, broccoli, and Brussels sprouts with lower risks of breast, prostate, lung, and colorectal cancers. Most people do not eat enough of these foods.

You also discussed sugar. I am currently following a ketogenic diet, and I wonder whether it is optimal for dementia, longevity, and aging. What are your views on the ketogenic diet?

Dr. Rhonda Patrick: There is the classical, extreme ketogenic diet and there are modified low-carbohydrate ketogenic diets. Modified versions can include leafy greens. Although leafy greens contain carbohydrate, they are high in fiber and have a low glycemic index, so a person can eat them and remain in ketosis.

I am very interested in the ketogenic diet because beta-hydroxybutyrate, the major circulating ketone body produced during ketosis, may be highly beneficial. Like lactate, it can enter the brain, provide an easily used energy source for neurons, and act as a signaling molecule.

Steven Bartlett: Ketones are what the body makes when a person abstains from carbohydrates and sugars.

Dr. Rhonda Patrick: Yes. The body eventually shifts into ketosis and runs on ketones.

Steven Bartlett: Beta-hydroxybutyrate is the ketone measured with a finger-prick test.

Dr. Rhonda Patrick: It is the major circulating ketone measured that way. It is also a signaling molecule that activates brain-derived neurotrophic factor in the brain. It is almost like having lactate in the body continuously.

I am especially interested in ketogenic diets for people who respond well. Some people experience substantial increases in triglycerides or cholesterol, so responses vary. It is useful to measure these markers and consider cycling the diet. I have been interested in cycling ketosis for potential brain benefits because beta-hydroxybutyrate can enter the brain and be used for energy instead of glucose.

Steven Bartlett: We should step back and explain keto for listeners who have never understood it. Many people do not know what keto or ketosis is.

Dr. Rhonda Patrick: At a high level, ketosis means that the body is using mostly fatty acids for energy and less glucose. The body still needs some glucose. Red blood cells, for example, do not have mitochondria and require glucose. Most energy, however, comes from fatty acids released from fat stored in adipose tissue.

Steven Bartlett: Such as the fat in my belly.

Dr. Rhonda Patrick: Yes, including visceral and subcutaneous fat.

Steven Bartlett: That sounds great. My body burns stored fat instead of the glucose from something such as bread, so I lose weight.

Dr. Rhonda Patrick: People do lose weight on a ketogenic diet.

Steven Bartlett: My father lost a remarkable amount of weight after a few months on a ketogenic diet. He went from having a large belly to weighing 13 stone for the first time since his teens. He lost about four or five stone and looks completely different. I am not saying he should stay on the diet forever, but the speed of his weight loss was remarkable.

Dr. Rhonda Patrick: A ketogenic diet is predominantly fat. The body uses both stored fat and dietary fat for energy, producing ketone bodies through a series of biochemical reactions.

A ketogenic diet is not the only way to enter ketosis. Fasting can also do it. When you are not eating, the body relies on stored energy. The liver has a limited amount of glucose stored as glycogen. After about 12 hours without food, with individual variation, liver glycogen becomes depleted and the body shifts toward lipolysis, or the breakdown of fat.

Long-duration exercise can also produce ketosis because endurance athletes deplete glycogen more quickly and use substantial energy. These approaches can be combined. Endurance exercise with a ketogenic diet can move a person into ketosis more quickly.

Steven Bartlett: Is it like a switch?

Dr. Rhonda Patrick: Metabolic flexibility is the body's ability to switch between using glucose and fatty acids for energy and producing ketones. People who regularly exercise, fast, practice time-restricted eating, or enter ketosis become accustomed to switching toward fatty-acid metabolism.

For example, a person might eat within an eight-hour window and then avoid food for 16 hours. Many people think they eat within 12 hours, but studies suggest that eating often spans 15 to 16 hours. It takes about 12 hours on average to deplete liver glycogen, although physical activity can accelerate it. After liver glycogen is depleted, the body shifts toward fatty-acid use and eventually ketosis.

Steven Bartlett: Have studies compared lifespan in animals on a ketogenic diet with animals eating an average diet?

Dr. Rhonda Patrick: Dr. Eric Verdin at the Buck Institute for Research on Aging published rodent studies around 2017 or 2018. A ketogenic diet appeared to extend lifespan and, more importantly, healthspan. The animals' brains aged better and showed fewer pathological features associated with Alzheimer's disease.

The effects are multifactorial. A person in ketosis generally consumes less glucose. Glucose can be damaging when a person is not physically active because activity helps direct it into muscle.

Steven Bartlett: Then it is not damaging the vascular system.

Dr. Rhonda Patrick: The vascular system is closely connected to the brain. Stiffer blood vessels, impaired blood flow, and hypertension can all affect brain aging. Studies also show that people with blood glucose at the high end of the normal range have more brain atrophy than people at the low end of normal.

Steven Bartlett: By brain atrophy, you mean the brain is shrinking.

Dr. Rhonda Patrick: Shrinking, especially in the hippocampus.

Steven Bartlett: That is the part of the brain involved in learning and memory.

Dr. Rhonda Patrick: Glucose can contribute to damage and accelerate aging. Beta-hydroxybutyrate also has an interesting role. It crosses into the brain through a monocarboxylate transporter and can serve as energy for neurons. Neurons can use glucose, but converting glucose into energy requires more energy than using beta-hydroxybutyrate, making the ketone an energetically favorable fuel.

When neurons use ketones, more glucose can enter the pentose phosphate pathway. That pathway provides precursors for glutathione, a major antioxidant in the brain. Oxidation and neuroinflammation contribute to brain aging, Alzheimer's disease, and dementia. More glutathione can help manage oxidative damage.

Beta-hydroxybutyrate is also a signaling molecule. Ketosis is a mild stress state produced through exercise, fasting, or a ketogenic diet. The body responds by activating stress-response pathways that can improve resilience. Beta-hydroxybutyrate activates brain-derived neurotrophic factor, which supports new neurons, neuronal connections, and neuroplasticity.

The proposed brain benefits therefore operate at several levels: less glucose exposure, more glucose available for antioxidant production, ketones as an efficient brain fuel, and activation of adaptive signaling pathways.