The Peter Attia Drive

#375 - 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.

December 8, 2025

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  • Nutritional ketosis is a physiologically defined state, marked by blood beta-hydroxybutyrate levels above 0.5 mmol/L, achieved through fasting or a carbohydrate-restricted ketogenic diet. 
  • The ketogenic diet is a powerful metabolic therapy with pleiotropic effects, historically proven to manage drug-resistant epilepsy, with efficacy rates around two-thirds in pediatric cases. 
  • The early exogenous ketone precursor, 1,3-butanediol, is analogous to consuming alcohol metabolically, potentially causing liver strain and generating toxic aldehyde intermediates when consumed in large doses necessary for therapeutic ketosis. 
  • Exogenous ketone supplementation, particularly ketone salts, can serve as an elegant bridge to mitigate the negative energetic and electrolyte-related side effects during the transition into nutritional ketosis, unlike ketone esters which carry risks of insulin spikes and subsequent hypoglycemia/hypoketosis at high doses. 
  • The D-enantiomer of BHB is rapidly metabolized for fuel, while the L-enantiomer, present in racemic mixtures, is metabolized slower and appears to retain important signaling functions related to neuroinflammation (like NLRP3 inflammasome inhibition), suggesting a potential benefit to using DL-mixtures. 
  • For cancer treatment, particularly glioblastoma, the goal of ketogenic metabolic therapy is to achieve and maintain a Glucose-Ketone Index (GKI) between 1 and 4 as an adjuvant to standard care, setting the stage for synergistic drug therapies that target glucose and glutamine metabolism in cancer cells. 
  • Situational fasting can be used for acute benefits like managing inflammation flares (shingles, GI issues) or enhancing focus during intense cognitive work. 
  • For acute concussion or brain injury, hyperbaric oxygen therapy (HBOT) protocols might involve 40 sessions at 2 atmospheres, 5 days a week for several weeks, though the commitment is significant. 
  • Rigorous, controlled studies, including a large DOD-funded trial at USF using sham controls, are ongoing to definitively assess the neuro-regenerative and cognitive benefits of HBOT for TBI and PTSD. 

Segments

Host Introduction and Guest Context
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(00:00:10)
  • Key Takeaway: Peter Attia’s Drive podcast is supported entirely by members to maintain an ad-free environment.
  • Summary: The podcast focuses on translating longevity science for accessibility, supported by premium memberships to avoid paid advertisements. Guest Dominic D’Agostino is a neuroscientist specializing in ketogenic diets, exogenous ketones, and hyperbaric oxygen. The episode promises to cover definitions of ketosis, exogenous ketone progression, and applications in cancer and neurodegenerative diseases.
Dom D’Agostino’s Scientific Journey
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(00:04:13)
  • Key Takeaway: D’Agostino’s research trajectory began with studying the neural control of respiration and oxygen toxicity, leading to his focus on the ketogenic diet as a nutritional countermeasure.
  • Summary: His initial neuroscience work focused on the brainstem network controlling respiration and its response to oxygen levels. A postdoctoral fellowship from the Office of Navy Research directed him to study central nervous system oxygen toxicity, which manifests as seizures. He pivoted back to the ketogenic diet because it effectively treats many seizure disorders where drugs fail.
Oxygen Toxicity in Military Diving
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(00:07:11)
  • Key Takeaway: High concentrations of oxygen, such as those used in closed-circuit rebreathers by Navy SEALs, can cause CNS oxygen toxicity leading to seizures due to excessive glutamate release and reactive oxygen species.
  • Summary: Oxygen toxicity is a risk in military diving when using closed-circuit rebreathers that supply 100% oxygen at depth, as it stimulates massive glutamate release and inhibits GABA production. This phenomenon has been known for over 100 years, but modern research, including studies pushing subjects to seizure in controlled settings, investigates how ketosis can increase latency to seizure.
Defining Nutritional Ketosis
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(00:14:53)
  • Key Takeaway: Nutritional ketosis is objectively defined as having blood beta-hydroxybutyrate (BHB) above 0.5 mmol/L, a state achieved by fasting or a high-fat, carbohydrate-restricted diet.
  • Summary: Ketosis is generated when insulin is suppressed, leading to accelerated fatty acid oxidation in the liver, producing BHB and acetoacetate to fuel the brain. The ketogenic diet, historically 90% fat, is now often modified to include higher, more appreciated levels of protein. This metabolic state results in pleiotropic effects across physiology and neuropharmacology.
Ketogenic Diet for Epilepsy
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(00:18:58)
  • Key Takeaway: The ketogenic diet is a highly efficacious therapy for drug-resistant epilepsy, capable of achieving complete seizure control in about one-third of pediatric patients.
  • Summary: The diet’s efficacy in epilepsy was first observed when fasting controlled seizures before anti-seizure drugs existed. In pediatric epilepsy refractory to drugs, two-thirds of patients respond therapeutically, with about one-third achieving near-complete seizure control. This effect is thought to stem from profoundly changing fuel systems, biochemistry, and neuropharmacology, potentially even curing some patients after prolonged adherence.
Personal Keto Experience and Mistakes
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(00:24:19)
  • Key Takeaway: Common mistakes entering nutritional ketosis include underestimating caloric intake and failing to track biomarkers, while maintaining adequate protein intake is crucial, especially for active individuals.
  • Summary: D’Agostino began tracking ketones around 2009 and noted initial strength loss due to insufficient protein intake, emphasizing that protein needs are higher than standard RDA recommendations for athletes. The top mistakes are failing to track total calories and macronutrients, as fat is calorically dense, and not monitoring blood ketone levels to correlate intake with physiological state.
Guidance on Carbohydrate Intake
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(00:41:28)
  • Key Takeaway: For weight loss on a ketogenic diet, focus should be on high protein, moderate fat, and ensuring consumed carbohydrates are high in fiber, which mitigates glycemic spikes.
  • Summary: When reintroducing carbohydrates after achieving fat adaptation, prioritizing fibrous vegetables like broccoli and asparagus is recommended, as fiber buffers the glycemic response. Metabolically flexible individuals can tolerate temporary carbohydrate increases, but abrupt reintroduction after strict restriction can cause GI distress, inflammation, and mood alteration due to rapid physiological shifts.
Carnivore Diet as Keto Variant
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(00:44:23)
  • Key Takeaway: The strict carnivore diet can induce ketosis if the fat-to-protein ratio is high enough, and it functions as the ultimate elimination diet, proving therapeutic for many autoimmune conditions.
  • Summary: A very fatty carnivore diet, especially when coupled with a caloric deficit, can lead to a ketotic state. This diet is compelling for autoimmune disorders because it removes all potential plant-based triggers, and animal products provide necessary micronutrients, though magnesium levels may trend low without plant sources.
Early Exogenous Ketone History
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(00:48:13)
  • Key Takeaway: The earliest exogenous ketone substance, 1,3-butanediol, is an alcohol precursor that elevates BHB but carries a risk of liver toxicity similar to chronic alcohol consumption due to overwhelming metabolic pathways.
  • Summary: 1,3-butanediol was historically studied by NASA as a shelf-stable, ketogenic food source that lowers blood glucose by inhibiting hepatic gluconeogenesis. However, consuming the large doses required for therapeutic ketosis can overwhelm the alcohol dehydrogenase enzyme, leading to the accumulation of damaging aldehyde intermediates and elevated liver enzymes.
1,3-Butanediol Toxicity Concerns
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(00:56:53)
  • Key Takeaway: High doses of 1,3-butanediol can overwhelm the liver’s enzymatic cascade, potentially generating toxic aldehyde intermediates and causing a narcotic ‘drunk’ effect.
  • Summary: Unlike nutritional ketosis, consuming large amounts of 1,3-butanediol can lead to the generation of aldehyde intermediates, which is potentially harmful. The compound also produces a noticeable narcotic effect, making it risky for frail individuals. This toxicity is why ketone esters were developed to bypass the need for large 1,3-butanediol loads.
Ketone Ester vs. Salt Development
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(00:58:22)
  • Key Takeaway: Ketone esters (like BHB bound to 1,3-butanediol) were developed to liberate ketones quickly, but the resulting 1,3-butanediol still enters the liver, causing potential toxicity and a secondary pharmacokinetic peak.
  • Summary: The glycerol BHB ester was created via transesterification of 1,3-butanediol and BHB to rapidly liberate the ketone, but the remaining 1,3-butanediol still requires liver processing. High doses of 1,3-butanediol can double liver enzymes even in healthy individuals and cause significant narcotic effects. The development of ketone salts avoided the 1,3-butanediol baggage entirely by using an ionic bond.
Ketone Salt Electrolyte Formulation
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(01:02:05)
  • Key Takeaway: Ketone salts utilize an ionic bond with positive cations (like sodium, potassium, calcium, magnesium) to offset the negative charge of BHB, and the lack of chloride mitigates the typical hypertensive risk associated with sodium chloride.
  • Summary: The initial development of ketone salts focused on combining BHB with various positive cations beyond just sodium to balance electrolyte intake, such as potassium and calcium. The hypertensive effects commonly associated with salt intake are primarily linked to sodium chloride, not the sodium found in salts like sodium beta-hydroxybutyrate. Ketone salts provide electrolytes crucial for replenishing losses during the initial phase of a ketogenic diet.
Ketone Salts vs. Esters for Transition
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(01:04:25)
  • Key Takeaway: Ketone salts are advantageous over esters for easing the transition into keto because their slower absorption rate prevents the rapid ketone spike that triggers a counterregulatory insulin dump, thus avoiding hypoglycemia and hypoketosis.
  • Summary: The early stages of keto involve an energetic gap where glucose utilization drops before ketone levels are sufficient, causing people to feel lousy; exogenous ketones can bridge this gap. Rapidly spiking ketones above 1.5 to 2 mM, as often happens with esters, can cause a counterregulatory insulin release, leading to subsequent hypoglycemia and hypoketosis. Ketone salts avoid this effect due to a slower rate of rise and the presence of minerals delaying gastric absorption.
D- vs. L-BHB Enantiomer Effects
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(01:09:30)
  • Key Takeaway: While D-BHB is energetically favorable for ATP production, L-BHB, which is metabolized much slower, appears to retain important signaling functions, such as inhibiting the NLRP3 inflammasome, making racemic mixtures potentially beneficial for both energy and signaling.
  • Summary: Ketone monitoring devices typically only measure the D-enantiomer, but the body produces a racemic mixture where L-BHB is metabolized three to four times slower. L-BHB concentrations are notably higher in the brain and may be responsible for epigenetic and signaling effects, whereas D-BHB is quickly burned for fuel. Pure D-BHB ester, in some early studies, trended toward accelerating seizure onset, suggesting the L-form plays a protective role.
NAD and Ketogenesis Connection
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(01:16:23)
  • Key Takeaway: Rapid spiking of D-BHB can cause reductive stress by depleting NAD via NADH production, whereas a ketogenic diet naturally boosts NAD, suggesting NAD elevation is a central mechanism in ketogenesis’s benefits.
  • Summary: The balance between BHB and acetoacetate is crucial for maintaining redox balance; rapidly elevating D-BHB can cause reductive stress by depleting NAD. A ketogenic diet is known to boost NAD levels, which is considered a central player in the benefits of ketogenesis. Current NAD supplementation (NR/NMN) has shown limited efficacy, possibly due to poor stabilization or liver uptake, but stabilized NAD compounds are being developed for conditions like oxygen toxicity.
Keto Therapy for Psychiatric Disorders
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(01:20:31)
  • Key Takeaway: There is emerging, highly funded research into using ketogenic diets, often supplemented with exogenous ketones for feasibility, to treat severe psychiatric disorders including anorexia, bipolar disorder, and schizophrenia.
  • Summary: The ketogenic diet is being investigated for psychiatric disorders due to its effects on neuropharmacology and mood stabilization, with dozens of clinical trials underway, largely funded by the Bazuki foundation. Adherence to a strict KD is difficult in these populations, leading researchers to incorporate exogenous ketone supplementation into trial designs. Promising case reports suggest ketogenic diets combined with ketamine may induce remission in anorexia.
Ketones vs. Diet for Performance
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(01:24:05)
  • Key Takeaway: Exogenous ketone supplementation cannot fully replicate all benefits derived from carbohydrate restriction, but it does lower blood glucose by decreasing gluconeogenesis and enhancing insulin sensitivity.
  • Summary: There are benefits derived from carbohydrate restriction that cannot be replicated solely by taking exogenous ketones. Ketone ingestion influences the liver in ways not fully understood, potentially decreasing gluconeogenesis and increasing insulin sensitivity for better glucose disposal. However, excessively high ketone levels (above 2-3 mM from supplementation) can lead to energy toxicity, insulin release, and acidosis, which is less likely with nutritional ketosis due to homeostatic mechanisms.
Cancer Therapy Framework Details
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(01:34:45)
  • Key Takeaway: Ketone metabolic therapy for highly glycolytic cancers like glioblastoma requires achieving a Glucose-Ketone Index (GKI) of 1 to 4 as an adjuvant to standard care, coupled with pharmacological targeting of glucose and glutamine pathways.
  • Summary: The framework for GBM treatment involves maintaining a GKI of 1 to 4 (e.g., Glucose at 4 mM, Ketones at 1 mM) to create an energetic crisis in cancer cells, triggering autophagy and cell death. This metabolic shift must be combined with drugs that inhibit glucose uptake (like hexokinase inhibitors) and drugs that target glutamine metabolism, as cancer cells can utilize glutamine when glucose is scarce. Clinical trials are ongoing, but the complexity of combining diet and multiple drugs makes execution challenging.
Alzheimer’s Energetic Crisis Rationale
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(01:45:45)
  • Key Takeaway: Alzheimer’s disease is characterized by brain glucose hypometabolism, and ketogenic therapies are rational because the brain’s capacity to use ketones is preserved with age, unlike its capacity to use glucose.
  • Summary: A hallmark of Alzheimer’s disease is glucose hypometabolism, suggesting that a subset of patients suffer from an energetic crisis that ketones can address by providing an alternative fuel source. Systemic inflammation is considered a major driver leading to neuroinflammation and subsequent amyloid/tau pathology. While acute ketone elevation improves cognition, long-term studies are needed to see if they halt amyloid progression, with patient selection based on glucose hypometabolism being a key factor.
Cognitive Stacks and Situational Fasting
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(01:53:45)
  • Key Takeaway: A beneficial cognitive stack often combines ketone delivery (MCTs), cholinergic support (Alpha-GPC), and stimulation (caffeine), while fasting should be used situationally rather than as a daily default.
  • Summary: Alpha-GPC, often paired with MCT and caffeine, is used situationally for long periods of cognitive demand, though high doses can cause overstimulation or sleep disruption for some. Fasting is recommended situationally—such as during periods of high paperwork or during inflammatory events like shingles—rather than being a daily default, as its benefits are maximized when addressing a specific stressor or deficit.
Situational Fasting Benefits
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(01:55:20)
  • Key Takeaway: Fasting can be situationally deployed to manage acute inflammation events like shingles or GI issues.
  • Summary: Situational fasting can be beneficial during inflammation events such as shingles or herpes simplex flare-ups. Individuals also report increased sharpness when fasting during periods of heavy administrative work, like grant reviews. This suggests fasting can be used strategically for acute cognitive or inflammatory support.
HBOT FDA Indications and Reality
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(01:55:44)
  • Key Takeaway: HBOT lacks FDA approval for common neurological issues like TBI and concussion despite anecdotal support.
  • Summary: The FDA indications for hyperbaric oxygen therapy primarily cover decompression sickness and wound healing for burn patients. There is no FDA approval for TBI, concussion, or general neuroprotection. Peter Attia generally advises against HBOT outside approved indications due to cost and hassle, but would consider it for his family after a concussion due to low downside risk.
Acute Concussion HBOT Protocol
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(01:57:02)
  • Key Takeaway: Acute concussion treatment may involve 40 sessions of HBOT at 2 atmospheres over several weeks.
  • Summary: For acute concussion within 48 to 72 hours, HBOT could be remarkably effective, especially for younger populations. A suggested protocol involves two atmospheres of oxygen for 60 to 90 minutes, five days a week, potentially totaling 40 dives over a period of about two months. This intensive commitment is why the recommendation is often cautioned against.
Soft Chamber and Chronic TBI Data
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(01:58:17)
  • Key Takeaway: None
  • Summary: Soft chambers operate around 1.3 atmospheres, potentially serving as a starting point for mild concussions or less intensive protocols (e.g., three times per week for two weeks). Emerging data suggests HBOT, using rigorous methods (1.5 to 2 atmospheres for 40-60 sessions), may increase cognitive function even years after a traumatic brain injury.
USF Rigorous HBOT Study
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(01:59:27)
  • Key Takeaway: A $30 million DOD-funded study at USF is using rigorous controls, including a sham control, to test HBOT for PTSD and brain injury.
  • Summary: The Aviv Clinic in The Villages has treated thousands of patients with reported cognitive function increases, though without TBI focus. The DOD funded a highly controlled study at USF using six chambers to test HBOT versus a sham control (pulsed pressure) for PTSD and brain injury. Preliminary data from this study is expected within the next year, aiming to provide systematic evidence.
Ketone Progress and Personal Diet Shift
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(02:03:14)
  • Key Takeaway: Exogenous ketone technology has exploded since the last discussion, offering alternatives to strict ketogenic dieting.
  • Summary: Peter Attia notes that while progress on cancer and Alzheimer’s treatments via ketogenic diets has been slow due to lack of trials, the field of exogenous ketones has exploded. Attia has personally stopped the discipline of a ketogenic diet but notes the remarkable benefits he previously experienced. He is now curious about trying supplemental ketone salts, especially given improved GI tolerance.
Exogenous Ketone Recommendation and Disclosures
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(02:04:37)
  • Key Takeaway: Dominic D’Agostino recommends ‘Keto Start by Audacious Nutrition’ ketone salts, noting his wife advises the company.
  • Summary: The recommended ketone salt product is ‘Keto Start by Audacious Nutrition,’ which is available on Amazon. D’Agostino is not financially involved in the company but his wife advises them. He also disclosed advising for Levels Health (CGM), MetPhys (metabolic psychiatry app), and previously Arx Sugar (allulose).