#375 - Ketogenic diet, ketosis & hyperbaric oxygen: metabolic therapies for weight loss, cognition, Alzheimer's & more | Dom D'Agostino, Ph.D.
Dom D'Agostino, a neuroscientist and professor, discusses metabolic therapies including ketogenic diets, exogenous ketones, and hyperbaric oxygen. He defines nutritional versus supplemental ketosis, outlines practical ways to achieve it, and explores its therapeutic potential for conditions like cancer, neurodegenerative diseases, and psychiatric disorders.
Deep Dive Analysis
15 Topic Outline
Dom D'Agostino's Scientific Journey into Ketosis
Navy's Interest in Oxygen Toxicity and Rebreather Diving
Defining Nutritional Ketosis and Its Historical Use
Dom's Personal Ketogenic Diet Experience and Lessons Learned
Common Mistakes and Guidance for Ketogenic Diets
Metabolic Implications and Efficacy of the Carnivore Diet
Evolution of Exogenous Ketones: Butanediol and Esters
Ketone Salts vs. Esters: Differences and Applications
Understanding D- and L-Beta-Hydroxybutyrate Enantiomers
NAD's Role in Ketosis and Challenges with Supplementation
Emerging Applications of Ketogenic Diets for Psychiatric Disorders
Cognitive and Performance Benefits of Ketone Supplementation
Ketogenic Metabolic Therapy Framework for Cancer (Glioblastoma)
Ketogenic Therapies for Alzheimer's Disease and Dementia
Hyperbaric Oxygen Therapy for Brain Injuries and Cognitive Function
9 Key Concepts
Central Nervous System Oxygen Toxicity
This condition manifests as seizures when breathing high concentrations of oxygen at depth, primarily due to excessive glutamate release, activation of AMPA and NMDA receptors, inhibition of glutamic acid decarboxylase (GAD), and a burst of reactive oxygen species in the brain.
Nutritional Ketosis
A physiological state achieved through fasting or a carbohydrate-restricted, high-fat diet, characterized by blood beta-hydroxybutyrate levels above 0.5 millimoles per liter. In this state, the body primarily uses ketone bodies for energy, especially for the brain.
Pleiotropic Effects
A term used to describe the multiple beneficial biochemical, physiological, and neuropharmacological mechanisms that are activated by ketogenic diets. These diverse effects contribute to the diet's therapeutic efficacy across various conditions.
Ketone Esters
Ketone bodies (like beta-hydroxybutyrate or acetoacetate) that are covalently bound to an alcohol, such as 1,3-butanediol or glycerol. When consumed, they are designed to rapidly and significantly elevate blood ketone levels, but can sometimes cause an insulin response or metabolic stress.
Ketone Salts
Ketone bodies (specifically beta-hydroxybutyrate) that are ionically bound to mineral cations like sodium, potassium, calcium, or magnesium. They elevate blood ketones more slowly and to a lesser extent than esters, without causing an insulin spike, and also provide essential electrolytes.
Racemic Ketones (DL-BHB)
A mixture containing both D-beta-hydroxybutyrate (the naturally occurring, rapidly metabolized form for energy) and L-beta-hydroxybutyrate (the mirror image, which is metabolized slower and appears to have important signaling effects, such as inhibiting neuroinflammation).
Glucose Ketone Index (GKI)
A biomarker used to assess the depth of ketosis and metabolic health, calculated as the ratio of blood glucose (in millimoles per liter) to blood ketones (in millimoles per liter). Lower GKI values indicate a deeper state of ketosis.
Reductive Stress
A condition that can occur when D-beta-hydroxybutyrate levels rapidly spike, leading to an increase in NADH relative to NAD. This can potentially deplete NAD and cause metabolic issues, which is why a balanced redox state (e.g., with acetoacetate) is important.
Glucose Hypometabolism
A hallmark characteristic of Alzheimer's disease where the brain's capacity to utilize glucose for energy declines over time. Importantly, the brain's ability to use ketones as an alternative fuel source remains preserved in these conditions.
11 Questions Answered
Navy SEALs use closed-circuit rebreathers for stealth, breathing 100% oxygen, which at depths like 100 feet of seawater, can cause central nervous system oxygen toxicity, manifesting as seizures. Research aims to understand and prevent these incidents.
Nutritional ketosis is a physiological state where blood beta-hydroxybutyrate levels are above 0.5 millimoles per liter. It's achieved by fasting or eating a carbohydrate-restricted, high-fat diet that suppresses insulin and mobilizes fatty acids for ketone production in the liver.
In pediatric epilepsy, about two-thirds of patients who have failed drug therapy respond therapeutically to a ketogenic diet, with about one-third achieving complete seizure control and some even experiencing a cure. In adults, the response rate is closer to 30-40%.
Common mistakes include not tracking total calories and macronutrients, underestimating fat intake, and not monitoring blood ketone levels to correlate diet with physiological state. It's also important to get blood work done to track lipid and insulin levels.
Yes, a carnivore diet, especially one focused on fatty cuts of meat and restricted calories, can induce ketosis. It may be therapeutically beneficial for individuals with autoimmune disorders due to its extreme elimination diet nature, providing all necessary micronutrients if eating nose-to-tail.
Ketone esters are covalently bound and lead to rapid, high ketone elevation, potentially causing an insulin response and metabolic stress. Ketone salts are ionically bound to minerals, providing a slower, lower ketone rise without an insulin spike, and also supply electrolytes, making them generally safer and more practical for most people.
While D-BHB is rapidly metabolized for energy, L-BHB is metabolized slower and appears to have important signaling effects, such as inhibiting neuroinflammation and contributing to epigenetic changes. This prolongs the beneficial effects of ketones and makes racemic mixtures advantageous for sustained ketone elevation.
No, excessively high ketone levels (above 2-3 millimolar from supplements) can lead to 'energy toxicity,' causing counter-regulatory insulin release, increased kidney burden, and blood acidification, which can be problematic and even dangerous in animal models.
For glioblastoma, a ketogenic diet is proposed as an adjuvant therapy, aiming to achieve and maintain a Glucose Ketone Index (GKI) of 1-4. This creates an energy crisis in cancer cells when combined with drugs that aggressively target glucose and glutamine metabolism, potentially extending survival and improving quality of life.
Ketogenic therapies address glucose hypometabolism, a hallmark of Alzheimer's, by providing an alternative fuel (ketones) to the brain. They also suppress systemic and neuroinflammation, improve glucose metabolism, and increase overall brain energy metabolism, especially for patients with significant glucose hypometabolism.
For acute concussion within 48-72 hours, a recommended protocol is 2 atmospheres of oxygen for 60-90 minutes, 3-5 days a week, for a total of 40 sessions. This is a significant time commitment but may offer potential benefits.
21 Actionable Insights
1. Prioritize Protein Intake
Ensure adequate protein intake on a ketogenic diet, especially if active or aiming for muscle gain, potentially doubling the recommended daily allowance. This prevents muscle loss and supports higher protein turnover.
2. Track Diet & Biomarkers
Track total calorie intake, macronutrient ratios, and blood ketone levels (or urine/breath) to correlate diet with physiological state. Additionally, regularly monitor lipids (triglycerides, HDL, ApoB, LDL), hemoglobin A1C, and insulin levels to assess metabolic health and manage potential adverse effects.
3. Mitigate Keto Flu with Electrolytes
Use ketone electrolytes (e.g., KetoStart) when initiating a ketogenic diet to replenish sodium and other electrolytes. This helps mitigate ‘keto flu’ symptoms, brain fog, and plasma volume contraction caused by the diet’s natriuretic and diuretic effects.
4. Gradual Keto Diet Transition
Transition to a ketogenic diet gradually over four to six weeks rather than abruptly. This approach improves adherence and can lead to more favorable health responses, potentially avoiding negative blood work or electrolyte issues.
5. High-Fiber Carb Choices
When consuming carbohydrates on a ketogenic diet, prioritize high-fiber sources like berries, broccoli, asparagus, and dark chocolate. Fiber helps prevent glycemic spikes and supports ketosis.
6. Situational Fasting Strategy
Employ fasting situationally for specific benefits rather than as a daily default. It can be particularly effective for managing inflammation events (e.g., shingles, GI issues), enhancing cognitive sharpness during demanding work, or adapting to travel.
7. Consider Carnivore for Autoimmune
For individuals with autoimmune disorders, consider a carnivore diet as an ultimate elimination diet. If following, ensure nose-to-tail eating to cover micronutrient needs (e.g., Vitamin C from liver) and consider magnesium supplementation.
8. Target GKI for Cancer Therapy
For metabolic therapy in cancer (e.g., glioblastoma), aim to achieve and maintain a Glucose Ketone Index (GKI) of 1 to 4. This GKI range sets the stage for other modalities to work by creating an energy crisis in cancer cells.
9. Ketone Salts for Supplementation
Prefer ketone salts (e.g., KetoStart by Audacious Nutrition) for exogenous ketone supplementation over ketone esters or 1,3-butanediol. Ketone salts do not cause an insulin spike, are generally safer as natural buffers, and provide sustained ketone delivery, especially when combined with MCT.
10. Optimal Exogenous Ketone Levels
When using exogenous ketones, aim to elevate blood beta-hydroxybutyrate levels to a ‘sweet spot’ of one to two millimolar. This range provides a significant increase in brain energy without risking energy toxicity or triggering counter-regulatory insulin responses.
11. Cognitive Enhancement Stack
For cognitive enhancement and sustained focus, consider a combination of alpha-GPC, MCT, caffeine, and theanine (e.g., in a product like Ketobrain). This stack provides energy, focus, and a calming effect for demanding cognitive tasks.
12. HBOT for Acute Concussion
For acute concussion, especially within the first 48-72 hours, consider hyperbaric oxygen therapy (HBOT) at 2 atmospheres for 60-90 minutes, 3-5 days a week, for up to 40 sessions. A milder protocol (1.3 atmospheres, 3 times/week for 2 weeks) can be considered for mild concussions.
13. Consult Dietitian for Clinical Keto
If using a ketogenic diet to manage a clinical condition, work with a knowledgeable registered dietitian. This ensures proper guidance and management of the therapeutic diet.
14. Reintroduce Carbs Slowly
If reintroducing carbohydrates after a period of low-carb eating, titrate them back in slowly, starting with fibrous vegetables. This helps avoid negative counter-regulatory effects, GI distress, and mood swings.
15. Avoid High-Dose 1,3-Butanediol
Avoid consuming large, chronic doses of 1,3-butanediol, especially if elderly or with compromised liver function. Large doses can cause liver enzyme elevation, aldehyde generation, and a narcotic (intoxicating) effect.
16. Assess Glucose Hypometabolism for AD
If considering ketogenic therapy for Alzheimer’s disease, prioritize patients who present with remarkable glucose hypometabolism in the brain. This patient selection criterion may lead to more favorable responses.
17. Comprehensive AD Metabolic Therapy
Approach Alzheimer’s disease management with a comprehensive metabolic therapy strategy that targets multiple contributing factors. This may involve a ketogenic diet or formula combined with various cofactors.
18. Use Ketones for Cognitive Deficit
Utilize ketones and other cognitive enhancers primarily in contexts of cognitive deficit or environmental stress. They tend to be most effective when addressing an existing deficit or stress rather than for already optimal function.
19. Consider Creatine Supplementation
Consider creatine supplementation, as it is used by Dom for its potential benefits on metabolic rate and performance.
20. Seek Stabilized NAD Forms
If considering NAD supplementation, seek stabilized forms that can effectively reach target tissues like muscle and brain. This may help overcome delivery problems and achieve desired benefits for performance or brain health.
21. Peter Attia Membership
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6 Key Quotes
The ketogenic diet is indeed a magical diet in the way that it remarkably changes our physiology. And there's no other diet that exists that can, for example, manage drug-resistant seizures.
Dom D'Agostino
The salt-sensitive hypertension that you get is pretty much associated with sodium chloride.
Dom D'Agostino
Higher ketones are not advantageous and I think potentially very problematic.
Dom D'Agostino
If you elevate beta-hydroxybutyrate in the blood one millimolar, that represents a 10% increase of available energy to the brain.
Dom D'Agostino
Your genes are not your destiny.
Peter Attia
As we age, our capacity to use glucose decreases over time, but that does not happen with ketones. Our brain's ability to use ketones over time is preserved.
Dom D'Agostino
2 Protocols
Ketogenic Diet for Weight Loss
Dom D'Agostino- Track total calories and macronutrients using a reliable app (e.g., Carbon app).
- Aim for a high protein intake, typically 20-30% of total calories, or potentially 1 gram per pound of body weight for active individuals.
- Consume moderate fat to meet caloric needs after protein and carbohydrate targets.
- Prioritize high-fiber carbohydrates (e.g., leafy vegetables, broccoli, berries, dark chocolate) to allow for 50-100 grams of total carbs daily if one-third are fiber.
- Monitor blood ketone levels (e.g., with a Keto Mojo device) to correlate dietary intake with physiological ketosis.
- Undergo regular blood work to track key biomarkers such as triglycerides, HDL, ApoB, LDL, hemoglobin A1C, and insulin levels.
- Consider a gradual transition to the ketogenic diet over 4-6 weeks to improve adherence and overall health responses, especially to manage electrolyte balance.
Acute Concussion Hyperbaric Oxygen Therapy
Dom D'Agostino- Initiate treatment as early as possible, ideally within the first 48 to 72 hours post-concussion.
- Administer 100% oxygen at a pressure of 2 atmospheres.
- Each session should last between 60 to 90 minutes.
- Perform sessions 3 to 5 days per week.
- Complete a minimum of 40 dives or sessions over the treatment period.