#05 - Dom D'Agostino, Ph.D.: ketosis, n=1, exogenous ketones, HBOT, seizures, and cancer
Peter Attia interviews Dr. Dominic D'Agostino, a neuroscience professor at the University of South Florida, about his research into ketogenic diets, exogenous ketones, hyperbaric oxygen treatment, and a metabolic approach to cancer, including N-of-1 experiments.
Deep Dive Analysis
15 Topic Outline
Dominic D'Agostino's Background and Early Research Interests
Developing Hyperbaric Atomic Force Microscopy
Cancer Cells and Oxidative Stress Under Hyperbaric Oxygen
The Warburg Effect: Cancer Metabolism Explained
Oxygen Toxicity Seizures in Diving and Hyperbaric Oxygen Therapy
Hyperbaric Oxygen Therapy: Approved and Emerging Applications
George Cahill's Starvation Ketosis Experiments
Ketone Body Production and Metabolism
MCTs: Mechanism, Benefits, and Personal Experimentation
Ketogenic Diet and Exogenous Ketones for Seizure Control
Exogenous Ketones: Salts vs. Esters, Racemic vs. Enantiomers
Dom's NASA NEMO Mission: Ketosis in Extreme Environments
The Metabolic Management of Cancer: Press-Pulse Protocol
Role of Oxidative Stress and Antioxidants in Cancer Therapy
Ketones as Epigenetic Drivers and HDAC Inhibitors
8 Key Concepts
Hyperbaric Atomic Force Microscopy
A technology developed by Dom D'Agostino that combines atomic force microscopy with a hyperbaric chamber, allowing for nanoscopic imaging of living cells under elevated pressure and oxygen levels. It provides insights into cellular changes like membrane topography and mitochondrial dynamics in extreme environments.
Warburg Effect
A phenomenon where cancer cells exhibit insufficient mitochondrial oxidative phosphorylation (respiration) with compensatory fermentation, primarily relying on glycolysis for ATP production even in the presence of normal oxygen. This means they convert glucose to pyruvate and then to lactate, rather than efficiently processing pyruvate in the mitochondria.
Ketone Bodies (BHB, AcAc, Acetone)
Three primary molecules produced by the liver during accelerated fat oxidation: beta-hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone. BHB is the most stable and predominant form, while AcAc can spontaneously decarboxylate to acetone, which is volatile and exhaled. BHB and AcAc are metabolically active fuels, whereas acetone has some neuroprotective effects at low levels.
Ketone Salts vs. Esters
Ketone salts are formed by an ionic bond between a ketone molecule (like BHB) and a monovalent or divalent cation (e.g., sodium, potassium, calcium, magnesium). Ketone esters involve a covalent bond, for example, between BHB or acetoacetate and 1,3-butanediol or glycerol, allowing for higher ketone concentrations and different metabolic pathways.
R vs. L Enantiomers
Stereoisomers that are mirror images of each other, like D-beta-hydroxybutyrate (D-BHB) and L-beta-hydroxybutyrate (L-BHB). The body predominantly produces D-BHB during nutritional or starvation ketosis, though a racemase enzyme can convert D to L. Many commercial ketone salts are racemic (equal D and L forms), while some esters are pure D-BHB.
Glucose Ketone Index (GKI)
A ratio of blood glucose to blood ketones (both measured in millimolar) used as a metabolic biomarker, particularly in cancer management. A lower GKI (e.g., 1:1 or 2:1) indicates a state of metabolic stress on cancer cells by limiting fermentable fuels and suppressing insulin.
Press-Pulse Protocol
A metabolic strategy for cancer management involving continuous 'press' protocols to metabolically stress cancer cells (e.g., calorie-restricted ketogenic diet, intermittent fasting, low-dose metformin) and intermittent 'pulse' protocols (e.g., hyperbaric oxygen, IV vitamin C, glycolytic inhibitors) to selectively kill stressed cancer cells.
Untitled Concept
Beta-hydroxybutyrate (BHB) functions not only as an energy source but also as a powerful signaling molecule that can epigenetically control gene transcription. It acts as a histone deacetylase (HDAC) inhibitor, influencing gene expression and potentially silencing pathological features in genetic disorders like Kabuki syndrome.
7 Questions Answered
At just 50 feet of seawater, within 10 minutes, divers using oxygen rebreathers run the risk of experiencing oxygen toxicity seizures due to high partial pressure of oxygen (PO2) in the brain.
HBOT can reverse tumor hypoxia, which is a driver of oncogenic activation, and by hyperoxygenating tumor tissue with damaged mitochondria, it skyrockets superoxide anion and oxidative stress, selectively triggering apoptosis and necrosis in cancer cells.
After about 7-10 days of fasting, the brain shifts from primarily using glucose to deriving approximately 60% of its energy from beta-hydroxybutyrate, 10% from acetoacetate, and only about a third from glucose, which is maintained at low levels through gluconeogenesis.
When consumed orally, MCTs are rapidly transported directly to the liver via hepatic portal circulation, bypassing chylomicron packaging, and are quickly oxidized by the liver's abundant mitochondria, leading to high rates of fat oxidation and ketone body production.
Yes, exogenous ketones cause a predictable and reliable decrease in blood glucose, often more significant than what is observed with metformin, potentially due to an exogenous ketone-induced release of insulin, increased insulin sensitivity, or a redox shift in the liver.
Yes, animal models show that exogenous ketones, particularly those that elevate both beta-hydroxybutyrate and acetoacetate (like 1,3-butanediol acetoacetate diester), can have significant anti-seizure effects even when added to a high-carbohydrate diet.
Many chemotherapeutic drugs and radiation therapy work by enhancing oxidative stress to kill cancer cells; therefore, antioxidants may block the efficacy of these treatments by counteracting the intended oxidative damage.
26 Actionable Insights
1. Seek Medical Guidance for Cancer
If afflicted by cancer, use the information discussed to identify appropriate clinical trials or pursue therapies under strict medical guidance, as podcast content is not medical advice.
2. Target Glucose Ketone Index 1-2
For cancer metabolic therapy, aim to maintain a Glucose Ketone Index (GKI) between 1 and 2, meaning blood glucose (in mmol/L) should be no more than twice the blood ketone level (in mmol/L).
3. Implement Supplemented Ketogenic Intermittent Fasting
To achieve and maintain a GKI of 1-2, practice supplemented ketogenic intermittent fasting by eating within a restricted window (e.g., 6 hours) and using exogenous ketones during the fasting window if needed.
4. Utilize Exogenous Ketones for GKI
If struggling to maintain a GKI of 1-2, consume exogenous ketones during fasting periods or even during feeding periods as a non-fermentable calorie source to help lower glucose and elevate ketones.
5. Hyperbaric Oxygen Therapy for Cancer
For GBM, consider hyperbaric oxygen therapy (HBOT) at 2.5 atmospheres for 60 minutes, three times a week, starting at low pressures (e.g., 1.5 ATA) and gradually increasing, while being aware of seizure risk.
6. Intravenous Vitamin C for Cancer
To enhance oxidative stress specifically in tumors, consider intravenous (IV) vitamin C (25-100 grams) as a pro-oxidant, especially when combined with hyperbaric oxygen therapy.
7. Avoid Antioxidants in Cancer Therapy
Avoid using antioxidant supplements during cancer therapy, as many treatments (like radiation and some chemotherapy) work by enhancing oxidative stress, and antioxidants may counteract their efficacy.
8. Consider Low-Dose Metformin for Cancer
Consider a low dose of metformin (starting at 500 mg/day, gradually increasing up to 2000 mg/day if tolerated) as part of a cancer metabolic therapy to activate AMP kinase, decrease insulin, and potentially increase ketones.
9. Use Glycolytic Inhibitors (Pulsed)
When using powerful glycolytic inhibitors like 2-deoxyglucose, 3-bromopyruvate, and lonitamine, implement a pulse protocol of two weeks on, two weeks off to maximize efficacy and minimize side effects.
10. Pulsed Low-Dose Insulin (Clinical)
In a clinical setting, consider a pulsed low-dose insulin IV to induce temporary hypoglycemia (1-2 mmol/L) to sensitize tumor tissue to other metabolic agents, especially when fermentable fuels are restricted.
11. Strong Ketosis for HBOT Safety
If undergoing hyperbaric oxygen therapy, especially with a brain injury, aim for strong nutritional ketosis to reduce the risk of CNS oxygen toxicity and seizures.
12. Consider Soft HBOT Chambers for TBI
For traumatic brain injury (TBI), consider using soft hyperbaric chambers (1.4-1.5 ATA) as a potentially safer alternative to high-pressure chambers.
13. Spread MCT Consumption for Tolerance
To increase MCT tolerance and ketone levels, spread MCT consumption throughout the day across multiple meals, incorporating it into foods like salad dressings or coffee.
14. Understand Racemic Ketone Salts
Be aware that most commercial ketone salts are racemic (contain both D and L forms), and while current research shows therapeutic benefits, the historical context of pharmacology suggests potential unknown risks with non-physiological enantiomers.
15. L-Form Ketones for Anti-Inflammation
When considering ketone supplements, note that racemic ketone salts, which include the L-form, may offer prolonged anti-inflammatory effects due to the L-form’s slower metabolism and longer presence in tissues.
16. D-BHB for Metabolic Fuel
For pure metabolic fuel, D-beta hydroxybutyrate (BHB) may have advantages over racemic forms.
17. Perform a Ketone Tolerance Test
Perform a ‘ketone tolerance test’ by ingesting a known amount of ketones and measuring blood BHB, glucose, insulin, and fatty acids at regular intervals (30, 60, 90, 120 minutes) to understand individual ketone utilization.
18. Use Urine Ketone Strips (Beginners)
Use urine ketone strips as a starting point to determine if you are in ketosis, especially for beginners.
19. Aim for 80 mg/dL Urine Ketones
Aim for a urine acetoacetate level of around 80 mg/dL on a urine ketone strip to confirm a state of ketosis.
20. Incorporate Low-Intensity Exercise/Mindfulness
Incorporate low-intensity exercise, meditation, and yoga into a cancer metabolic therapy plan to support overall well-being and potentially enhance therapeutic effects.
21. Immerse and Self-Experiment for Learning
Immerse yourself in what you’re doing and engage in self-experimentation to learn effectively and gain deeper insights.
22. Explore Ketonutrition.org
Visit ketonutrition.org for information on ketogenic nutrition, including podcasts, nutrition consultants, resources like the Charlie Foundation, and blog posts on ketone supplements and self-experimentation.
23. Attend Metabolic Health Summit
Attend the Metabolic Health Summit (Jan 30-Feb 3, Long Beach, CA) to learn about basic science, clinical applications, and new technologies in metabolic health and nutritional ketosis from experts and industry leaders.
24. Follow Dom D’Agostino on Social Media
Follow Dominic D’Agostino on Twitter (@DominicDagosti2) and Facebook (@DominicDagostino1) for updates and information.
25. Utilize Podcast Show Notes/Timestamps
Pay attention to show notes and use timestamps to navigate the podcast like a buffet, going directly to topics of interest.
26. Skip Technical Podcast Sections
If the podcast becomes too technical, do not hesitate to skip ahead to later sections that may be more relevant or easier to follow.
6 Key Quotes
I knew from the question that that guy knows what he's talking about.
Peter Attia
Cancer cells have elevated rates of reactive oxygen species that they use for growth and proliferation and also fuels metastasis and invasiveness of cancer cells.
Dominic D'Agostino
The Warburg effect simply stated is insufficient mitochondrial oxidative phosphorylation or what we call respiration with compensatory fermentation in the form of establishing the cell establishes its energy, its production of ATP, our energy currency through glycolysis and substrate level phosphorylation.
Dominic D'Agostino
The maintenance of glucose is under very powerful homeostatic mechanisms. So we have, we're hardwired from an evolutionary perspective to maintain glucose.
Dominic D'Agostino
I think anything that pushes glucose that low and ketones that high. And I think not really without knowing it, we're pretty task loaded. So you don't have all the time, you know, that much time to eat. I mean, part of the mission is that they're training.
Dominic D'Agostino
I think mitochondrial health and mitochondrial vitality would be the ultimate tumor suppressor.
Dominic D'Agostino
2 Protocols
Ketone Tolerance Test
Dominic D'Agostino- Measure fasting levels of BHB, glucose, insulin, and fatty acids.
- Ingest a known amount of exogenous ketones.
- Measure BHB, glucose, insulin, and fatty acids at 30, 60, 90, and 120 minutes post-ingestion.
Metabolic Management of Cancer (Press-Pulse Protocol)
Dominic D'Agostino- **Press Protocol (Continuous Metabolic Stress):** Achieve and maintain a Glucose Ketone Index (GKI) of 1:1 to 2:1 (glucose to ketone ratio in millimolar).
- Implement a calorie-restricted ketogenic diet, potentially with intermittent fasting.
- Consider low-dose metformin (e.g., 500-2000 mg/day, starting low and titrating up).
- Incorporate low-intensity exercise, meditation, and yoga.
- **Pulse Protocol (Intermittent Targeted Killing):** Utilize modalities tactically to kill cancer cells after metabolic stress.
- Hyperbaric Oxygen Therapy (HBOT): Administer at the maximum tolerable dose, 2.5 atmospheres for 60 minutes, three times per week (allowing a day off for adaptive effects).
- Intravenous (IV) Vitamin C: Administer at high doses (e.g., 25-100 grams) to act as a pro-oxidant, driving oxidative stress.
- Consider cancer-specific glycolytic inhibitors: 2-deoxyglucose (2DG) at ~25 mg/kg, 3-bromopyruvate, or lonitamine (hexokinase 2 inhibitor). These powerful drugs may be used in a two-weeks-on, two-weeks-off cycle.