The Peter Attia Drive – Episode #375

Title: The ketogenic diet, ketosis, and hyperbaric oxygen: metabolic therapies for weight loss, cognitive enhancement, cancer, Alzheimer's disease, brain injuries, and more | Dominic D'Agostino, Ph.D.
Date: December 8, 2025
Host: Peter Attia, MD
Guest: Dominic D’Agostino, Ph.D.

Overview

This episode brings back Dr. Dominic D’Agostino, a neuroscientist and leading researcher in the field of metabolic therapies, to discuss the latest developments and understandings around ketogenic diets, exogenous ketones, and hyperbaric oxygen therapy. Together with Dr. Attia, Dom dissects the science, clinical evidence, practicalities, and nuances behind using these metabolic interventions for weight loss, athletic performance, neurological diseases, cancer, mental health, and beyond. The conversation maintains a blend of deep biochemical knowledge, clinical practicality, and a tone that is both evidence-based and exploratory.

Key Discussion Points & Insights

1. Dom’s Scientific Journey & The Navy Connection

• Dom’s academic background started in neuroscience and nutrition, eventually leading to Navy-funded research on oxygen toxicity in divers using closed-circuit rebreathers ([04:24]-[09:16]).
• The path led to the ketogenic diet due to its efficacy against drug-resistant seizures—a core challenge in high-pressure oxygen environments ([05:49]-[07:11]).
• Early Navy and military research offers unique insight into how metabolism adjusts under extreme environments.

Quote:
"Everybody told me this is the dumbest thing to do. You can't get NIH funding with ketogenic. Nobody heard of the ketogenic diet." – Dom ([05:13])

2. Ketosis: Definitions & Mechanisms

• Nutritional ketosis: Achieved through fasting or carbohydrate-restricted, high-fat diets; physiological threshold is blood β-hydroxybutyrate >0.5 mmol/L ([15:23]-[17:48]).
• Importance of adequate protein—modern understanding refutes early ketogenic diets that restricted protein too heavily ([16:56]-[17:37]).
• Pleiotropic (“multi-mechanism”) effects of ketosis, most dramatically seen in its anti-seizure properties ([18:57]-[19:57]).

Quote:
"No other diet can, for example, manage drug resistant seizures. And it does that because it profoundly changes our fuel system, our physiology, our biochemistry, and our neuropharmacology." – Dom ([18:35])

3. Clinical Efficacy: Seizures & Beyond

• The ketogenic diet is profoundly effective for pediatric epilepsy (two-thirds respond, one-third become seizure free). In adults, efficacy is about 30–40% ([21:03]-[21:56]).
• Super-responders—some become seizure-free and can discontinue the diet with lasting remission ([21:56]-[22:57]).
• Possible curative mechanism may involve reducing the “kindling effect” (where seizures beget more seizures) by promoting network stability and reducing inflammation ([22:57]-[23:57]).

4. Transitioning to and Formulating a Ketogenic Diet

• Most common mistakes: Failing to track food intake and ketone levels; underestimating calories (especially from fat); inadequate electrolytes leading to "keto flu" ([27:06]-[28:00]).
• Protein: Dom recommends 20–30% protein by calories, sometimes up to 1g/lb of body weight, higher than the RDA—especially important for athletes and preserving lean mass ([38:23]-[40:39]).

Quote:
"Protein is really important and it was underappreciated in the early ketogenic diets. In the context of sports, it’s extremely important." – Dom ([17:19])

5. Practical Dietary Guidance & Personal Experience

• Carbohydrates: High-fiber, low-glycemic carbs can sometimes be included up to 50–100g/day, emphasizing fibrous vegetables like broccoli, cucumber, asparagus ([34:10]-[35:14]).
• Track with apps like Carbon, compare calculated vs. actual calorie intake—people often underestimate ([35:15]-[35:44]).
• Satiety and hypopalatable nature of keto, especially high protein: “You’re not going to overeat a ketogenic diet..." ([36:42]-[37:54])

6. Carnivore Diet as Ketogenic Variant

• Carnivore diets (meat only) can also induce ketosis, especially with fatty cuts and/or caloric restriction. Dom sees therapeutic utility especially for autoimmune disorders ([45:12]-[48:12]), though micronutrient deficiencies must be considered.

Quote:
"Carnivore diet is the ultimate elimination diet. Steak and animal-based protein has pretty much all the micronutrients... surprisingly." – Dom ([45:31]-[46:11])

7. Exogenous Ketones: Salts, Esters, and MCTs

Types, Biochemistry, and Practical Differences ([48:12]-[69:31])

• 1,3-Butanediol: Highly ketogenic, but metabolized like alcohol, can raise liver enzymes if overdosed ([52:17]-[57:44]).
• Ketone Esters: E.g., BHB monoester, butanediol-acetoacetate diester—allow rapid elevation of BHB; can overwhelm metabolism, potentially leading to "energy toxicity" at high levels ([58:21]-[66:37]).
• Salts: BHB bound ionically to cations (sodium, potassium, calcium, magnesium); slower, safer elevations in ketones with added electrolytes, no rapid insulin spike ([62:10]-[67:06]).
• MCT Oil: Still valued for its ability to induce endogenous ketosis and prolong ketone elevation when paired with exogenous ketones.

Quote:
"It's great, and actually I think [1,3-butanediol] has applications for cancer ... but drinking 1,3-butanediol to elevate BHB is somewhat analogous to drinking alcohol to generate acetate, which is a great molecule. But it's a very indirect way to do it that comes with toxicity." – Dom ([57:47]-[58:21])

• Ketone Enantiomers (D vs. L): D-BHB is used for energy; L-BHB has slower metabolism and may have unique signaling effects, particularly anti-inflammatory ([70:00]-[74:48]).

Quote:
"The D gets burned up quickly for fuel, then the L that kind of hangs around ... but then that's hitting the various receptors...you get the benefits of the D and then you get the signaling benefits of the L." – Dom ([71:57])

Practical Applications

• For cognitive and performance benefit, ketone salts are safer, easier to tolerate, and with improved taste and GI profile compared to early products ([69:31]-[70:00], [124:37]-[124:56]).
• Optimum serum BHB: Typically target 1–2 mmol/L for functional benefit without risk of "energy toxicity" ([69:09]-[69:31], [86:06]-[88:05]).
• Overelevation (>2–3 mmol/L) with supplements, especially esters, can cause insulin spikes, hypoglycemia, and acidosis ([63:07], [86:04]-[88:05]).

8. Clinical Applications: Cancer & Dementia

Cancer ([95:02]-[105:14])

• Focus on glioblastoma (GBM): Recognizes no therapy is curative, but ketogenic and multi-agent metabolic therapy may double or triple survival, especially when combined with other drugs targeting glycolysis and glutaminolysis.
• Need for well-designed clinical trials—the main obstacle to adoption is funding and logistical challenges ([102:08]-[105:14]).

Quote:
"The way to do the clinical trial, which has not been done yet, is to achieve and maintain a glucose ketone index of 1–4. That has never been done." – Dom ([98:14])

Dementia/Alzheimer’s & Cognitive Disease ([106:22]-[113:47])

• Glucose hypometabolism is a hallmark; subset of patients may improve dramatically with ketosis or exogenous ketones.
• Ongoing randomized studies suggest benefit especially in mild cognitive impairment with pronounced glucose hypometabolism.
• Anti-inflammatory effects, improved energy delivery, and possible modification of disease course ([109:22]-[113:47]).

Quote:
"The advantage of ketogenic metabolic therapies for Alzheimer's disease is really hinging upon suppressing inflammation, improving glucose metabolism, and elevating ketones to increase symptomatically brain energy metabolism." – Dom ([108:11])

9. Other Emerging/Evidence-Based Uses

• Psychiatric Disorders: Several ongoing trials funded by the Bouzucki Foundation for bipolar, schizophrenia, anxiety, anorexia, and more ([81:03]-[83:14]). Early signs are promising.
• Situational Use of Fasting and Ketosis: Useful as a tool for cognition, travel, inflammation—intermittently more effective and sustainable for most ([114:21]-[115:40]).

10. Hyperbaric Oxygen Therapy (HBOT)

• Background: 14 FDA-approved uses (e.g., wound care), but unapproved as yet for TBI, concussion ([07:31]-[08:03],[115:40]-[123:09]).
• Acute Concussion/TBI: Early use (within 48–72 hours) may confer benefit, especially in children, but protocols are logistically challenging (e.g., 40 sessions in 2 months) ([117:17]-[118:16]).
• Long-Term Cognitive/Mood Disorders: Anecdotal reports and emerging clinical trials (especially in veterans with PTSD/TBI) are underway ([120:26]-[121:41]).
• Study Rigorousness: New DOD-funded protocol includes true sham arms to finally clarify effectiveness ([121:41]-[123:09]).

Notable Quotes & Moments

• On the Ketogenic Diet’s Uniqueness:
  "It is indeed a magical diet in the way that it remarkably changes our physiology." – Dom ([18:32])

• On Energy Toxicity from Exogenous Ketones:
  "Higher ketones are not advantageous and I think potentially very problematic." – Dom ([86:04])

• On Exogenous Ketone Salts:
  "The salt does not produce that [insulin] effect at all..." – Dom ([66:42])

• On Funding & Clinical Trials:
  "Who's going to fund this clinical trial? ... To run a clinical trial with dietary therapies, you have to have oncologists who are savvy and knowledgeable about ketogenic diets, you have to have an RD team...The pharmaceutical companies are scrambling to get their drug into that patient..." – Dom ([103:12])

Timestamps for Important Sections

• Origins of Ketogenic Research & Navy Science: [04:24]–[09:16]
• Defining Ketosis, Diet, and Protein Needs: [15:23]–[21:56], [38:23]–[40:39]
• Seizure Control & Clinical Efficacy: [21:03]–[24:19]
• Practical Diet Tips, Mistakes, & Tracking: [27:06]–[38:23]
• Carnivore Diet Discussion: [45:12]–[48:12]
• Exogenous Ketone Biochemistry: [48:12]–[59:50], [62:10]–[70:00]
• D vs. L BHB, MCT, Use Cases: [70:00]–[75:00]
• Energy Toxicity Cautions: [86:04]–[89:14]
• Cancer Therapy—Framework and Frustrations: [95:02]–[105:14]
• Alzheimer’s & Cognitive Impairment—Mechanisms and Trials: [106:22]–[113:47]
• Psychiatric Disorders & Fasting: [81:03]–[83:53], [114:21]–[115:40]
• Hyperbaric Oxygen—Protocols & Clinical Trials: [115:40]–[123:09]
• Ketone Supplement Brands and Practical Advice: [124:37]–[124:56]

Resources, Recommendations, & Where to Find Dom

• Ketone Supplement (no financial ties):
  Keto Start by Audacious Nutrition ([124:37]-[124:56])
• Educational Projects:
  • Metabolic Health Initiative
  • Metabolic Link Podcast
  • Keto Nutrition (Info Site)
• Dom’s Podcast: Metabolic Link
• Continuous Ketone Monitoring Devices: SyBio CGM discussed, others in development ([29:24]-[30:31])

Closing Thoughts

The episode stands as a masterclass on the science and practical use of modified metabolic states—especially ketosis—for a diverse array of health, disease, and performance contexts. The dialogue blends high-level mechanistic insights with clear, actionable advice, all while underscoring the gap between exciting theoretical promise and the slow pace of clinical adoption and validation.

For further details and links referencing specific products and ongoing research, see Peter Attia’s show notes.