375 - The ketogenic diet, ketosis, and hyperbaric oxygen: weight loss, cognition, cancer, and more

Episode Overview

• Dom D'Agostino shares his unique journey from researching oxygen toxicity in Navy SEALs to becoming a leading authority on the ketogenic diet and ketone metabolism as a countermeasure for seizures.
• The discussion covers the practical application of ketogenic diets, including common mistakes like insufficient protein intake and the failure to track macros, and distinguishes between clinical protocols and casual "internet keto."
• The conversation delves into the biochemistry of various exogenous ketone supplements, explaining the liver toxicity of precursors like 1,3-butanediol and the distinct roles of D-BHB (energy) versus L-BHB (signaling).
• The speakers explore the therapeutic potential of metabolic strategies for major diseases, outlining the "press-pulse" theory for cancer and the rationale for using ketones to fuel the brain in Alzheimer's disease.
• A central theme is the significant gap between promising mechanistic research on metabolic therapies and the persistent lack of funding and large-scale clinical trials needed to validate their efficacy in humans.

Key Concepts

• CNS Oxygen Toxicity: Dom's initial research focused on preventing seizures caused by high-pressure oxygen (hyperoxia) in Navy SEALs, which led him to investigate the neuroprotective and anti-seizure properties of the ketogenic diet.
• Ketogenic Diet Pitfalls: The most common mistakes people make when adopting a ketogenic diet are failing to track calories and macros, and under-consuming protein, which can lead to muscle loss despite being in ketosis.
• Clinical vs. Internet Keto: A distinction is made between a "prescription metabolic therapy" (clinical keto) designed for specific therapeutic outcomes and a loosely defined "internet keto" that often lacks rigor.
• Carnivore as an Elimination Diet: The carnivore diet is framed as an extreme version of a ketogenic diet that acts as the "ultimate elimination diet," making it potentially therapeutic for autoimmune conditions sensitive to plant compounds.
• Exogenous Ketone Precursors: Early ketogenic substances like 1,3-butanediol are not ketones themselves but precursors that must be metabolized by the liver via the alcohol dehydrogenase pathway, which can cause liver stress and toxicity analogous to ethanol consumption.
• D-BHB vs. L-BHB Enantiomers: The two forms of beta-hydroxybutyrate have distinct functions. D-BHB is the primary energetic ketone metabolized quickly for ATP. L-BHB is metabolized slowly and acts as a potent, long-lasting signaling molecule that suppresses inflammation via the NLRP3 inflammasome.
• Reductive Stress: Rapidly elevating blood ketones with a pure D-BHB supplement can cause "reductive stress" by consuming NAD+ to form NADH, which is the opposite of the NAD+-boosting effect seen with endogenous ketosis from a ketogenic diet.
• Glucose Hypometabolism in Alzheimer's: A core feature of Alzheimer's disease is the brain's declining ability to utilize glucose for energy. However, the brain's capacity to use ketones as an alternative fuel source remains preserved with age.
• Press-Pulse Cancer Theory: A proposed metabolic cancer therapy that involves creating sustained metabolic stress on cancer cells (the "press" via a ketogenic diet) combined with acute, targeted therapies that inhibit cancer's primary fuels, glucose and glutamine (the "pulse").
• Research Funding Gap: A major obstacle to validating metabolic therapies for cancer and neurodegenerative disease is the lack of funding for large-scale, randomized controlled trials on non-patentable interventions like dietary protocols.

Quotes

• At 1:22 - "I believe Ken Ford connected us back in 2011-ish, thereabouts. At the time, I was about a year into experimenting with a ketogenic diet." - Peter Attia recounts how his early personal journey with ketosis led him to connect with Dom D'Agostino.
• At 3:23 - "I got a fellowship, a postdoctoral fellowship by the Office of Navy Research... to understand the cellular and molecular mechanisms of central nervous system oxygen toxicity, which manifests as seizures." - Dom D'Agostino details how he received funding from the Department of Defense to research oxygen-induced seizures, a key problem for Navy divers.
• At 3:40 - "I pivoted and went back to the ketogenic diet because the ketogenic diet works for many different seizure disorders when drugs fail." - Dom D'Agostino on why he shifted his focus from developing drugs to studying the ketogenic diet as a way to prevent seizures.
• At 3:55 - "Everybody told me this is like the dumbest thing to do... You can't get NIH funding with, you know, ketogenic. Nobody heard of the ketogenic diet back then." - Dom D'Agostino describes the academic resistance he faced when choosing to research the ketogenic diet in 2007-2008.
• At 23:32 - "So seizures beget seizures. So once you have a seizure... you're more likely to have another seizure." - Dom D'Agostino explains the "kindling effect" and the rationale for using ketogenic therapies to control epilepsy.
• At 26:45 - "I also learned the lesson that protein was really important. I was thinking ketones would be basically save, you know, muscle... but they don't." - Dom D'Agostino describes how his early personal experience with the ketogenic diet taught him that adequate protein intake is essential to prevent muscle loss.
• At 28:27 - "[The most common mistake is] not tracking. I mean people do it, they're just like, oh, I'm just going to eat, you know, this or that and not track." - Dom D'Agostino identifies what he believes is the number one mistake people make when attempting a ketogenic diet.
• At 36:41 - "For weight loss, I would say high protein, moderate fat, and then high fiber. So the carbohydrates that you're getting should be just fibrous carbohydrates." - Dom D'Agostino outlines his general formula for a ketogenic diet aimed specifically at weight loss.
• At 52:55 - "A carnivore diet is fundamentally, if practiced the way they do with Paleomedicina... a version of a ketogenic diet. And I think that's why it works." - Dom D'Agostino clarifies the metabolic link between a high-fat carnivore diet and a standard ketogenic diet.
• At 55:20 - "Everybody is talking about these things as though they're the same, and they're categorically not the same... and most people who are selling these things are not being transparent about what it is you're buying." - Peter Attia emphasizes the critical need for consumers to understand the biochemical differences between various ketone supplements.
• At 58:00 - "You can consume 1,3-butanediol... it goes through the alcohol dehydrogenase pathway and produces, much like alcohol... and it needs to be metabolized by the liver." - Dom D'Agostino details the metabolic pathway for 1,3-butanediol, drawing a direct parallel to how the body processes ethanol.
• At 82:48 - "The L seems to have... retains signaling effects that D does." - D'Agostino highlighting the key advantage of L-BHB, which, due to its slower metabolism, can exert sustained signaling effects.
• At 83:08 - "It's like the, almost like the drug form of BHB." - D'Agostino describing L-beta-hydroxybutyrate's role as a potent signaling molecule that persists in the body longer than its energetic counterpart, D-BHB.
• At 83:58 - "They only measure the D. They do not measure the L." - D'Agostino stating a critical limitation of current continuous ketone monitors and standard blood meters, which cannot detect L-beta-hydroxybutyrate.
• At 86:13 - "When you rapidly spike D-beta-hydroxybutyrate, you're causing something called reductive stress... you're depleting NAD." - D'Agostino explaining the potential negative metabolic consequence of using a pure, fast-acting D-BHB supplement.
• At 111:18 - "The way to... do the clinical trial is... to achieve and maintain a glucose ketone index of one to four. Like that has never been done." - Dom D'Agostino outlines the specific, rigorous methodology required for a proper clinical trial on ketogenic therapy for cancer.
• At 112:08 - "You could take glucose out of cell media and put in glutamine and maintain cancer cells in glutamine without glucose." - Dom D'Agostino explains why it's critical to target glutamine in addition to glucose, as cancer cells can adapt and use it as an alternative fuel source.
• At 114:30 - "None of this has been demonstrated clinically. This is all... extracting mechanistically from what we think these things do." - Peter Attia highlights the critical gap between the theoretical understanding of metabolic therapies and the lack of robust clinical evidence.
• At 114:47 - "So what's the hold up, right? I interviewed Tom [Seyfried] seven years ago and we had this exact same conversation." - Peter Attia expresses his frustration with the lack of progress in initiating the necessary clinical trials for metabolic cancer therapies.
• At 128:27 - "As we age, our capacity to use glucose decreases over time, but that does not happen with ketones. So our brain's ability to use ketones is preserved." - Dom D'Agostino explains the fundamental rationale for using ketones to treat neurodegenerative diseases like Alzheimer's.

Takeaways

1. Prioritize adequate protein on a ketogenic diet, as ketones alone are not sufficient to prevent muscle loss.
2. For consistent results, especially for weight loss, meticulously track your calories and macronutrient intake.
3. Tailor your ketogenic diet to your specific goal; a high-protein, moderate-fat, high-fiber version is often best for general health and weight management.
4. Consider the carnivore diet as a potential therapeutic tool for autoimmune conditions, viewing it as an ultimate elimination strategy.
5. Be highly critical of ketone supplements containing precursors like 1,3-butanediol, as they can impose a toxic load on the liver similar to alcohol.
6. Understand that not all exogenous ketones are created equal; investigate the specific type (ester, salt, racemic mixture) before use.
7. Opt for racemic (DL) ketone supplements over pure D-BHB to gain the benefits of both rapid energy (D-form) and sustained anti-inflammatory signaling (L-form).
8. Avoid high, frequent doses of pure D-BHB supplements to prevent "reductive stress" and the counterproductive depletion of NAD+.
9. Recognize that your ketone meter provides an incomplete picture by only measuring D-BHB, completely missing the important signaling molecule L-BHB.
10. Support and advocate for well-designed clinical trials for metabolic therapies to bridge the gap between promising theories and proven clinical application.
11. View ketosis as a proactive strategy for brain health, as ketones provide a reliable fuel source for the brain when its ability to use glucose declines with age.
12. Appreciate that for a metabolic cancer therapy to be effective, it must target both glucose and glutamine pathways, as cancer can adapt to use either fuel.