#05 - Dom D’Agostino, Ph.D.: ketosis, n=1, exogenous ketones, HBOT, seizures, and cancer

KEYPOINTS

• 01

  D'Agostino came to ketones through diving physiology and a lab accident.

  His PhD was on how brainstem neurons sense oxygen and CO2. His postdoc built a hyperbaric atomic force microscope, funded through the Department of Defense, to image living cells under pressure. Around 2008–09, while testing different fuels in cell culture, he noticed cancer cells grew more slowly in 1, 2 and 5 mM beta-hydroxybutyrate (BHB) at the same glucose level, and sped up again when the ketones were removed.

• 02

  Cancer cells sit on a knife-edge of oxidative stress.

  He describes a U-shaped curve. Tumor cells use elevated reactive oxygen species to grow, spread and invade, but because their mitochondria are dysfunctional, pushing oxidative stress further with high-pressure oxygen or chemotherapy can exceed their antioxidant capacity and trigger cell death. He says he saw this directly under the hyperbaric microscope, which no one had used for that purpose before.

• 03

  Seizures from oxygen toxicity limit Navy rebreather divers.

  A closed-circuit Dräger rebreather leaves no bubbles, which allows stealthy dives, but D'Agostino says about 10 minutes at 50 feet of seawater can trigger a seizure in some divers. He puts brain oxygen pressure at roughly 2,000 times normal. Susceptibility varies with genetics, sleep loss, diet and illness. He notes seizures are likely underreported, because SEALs are known for hiding health problems that could get them removed.

• 04

  In his research, ketone esters greatly increased resistance to oxygen-toxicity seizures.

  He says a ketone ester increases resistance by roughly 600%, and that exogenous ketones added to standard high-carb rat chow also protected against chemically induced and absence seizures in animal models. He thinks pairing a ketone ester with hyperbaric oxygen (HBOT) could make HBOT safer and more effective, though this is still a hypothesis for people.

• 05

  HBOT has about 14–15 approved uses and a powerful effect on stem cells.

  Approved uses include decompression sickness, carbon monoxide poisoning, radiation necrosis, noise-induced hearing loss and diabetic wounds. D'Agostino estimates diabetic wounds make up over 90% of hyperbaric facility revenue. He says HBOT mobilizes stem cells about as strongly as drugs like Neupogen. Traumatic brain injury is the most controversial use, and he would want to test low-pressure HBOT soon after injury combined with ketones.

• 06

  Ketones act as signaling molecules, not just fuel.

  Beyond replacing glucose for the brain, D'Agostino describes BHB acting as an HDAC inhibitor with epigenetic effects and suppressing the NLRP3 inflammasome in ways unrelated to metabolism. He began with the classic 4:1 ketogenic diet, about 90% fat, from the Johns Hopkins protocols, but reached only about 2–2.5 mM. He later moved to a modified diet with more protein plus MCTs.

• 07

  MCTs, especially C8, raise ketones because they go straight to the liver.

  Medium-chain fats bypass the chylomicron and lymphatic route and travel through the portal vein to the liver, where they are quickly oxidized. He says two to three tablespoons can raise BHB to about 0.5–1 mM even on a high-carb diet, and pure C8 raises it about 20–30% more than a C8/C10 mix. Attia notes that stomach upset often limits the dose before ketones get very high.

• 08

  Exogenous ketones reliably lower blood glucose, and why isn't settled.

  In rats, the maximum tolerated ketone-ester dose dropped glucose from about 140–150 to around 40 mg/dL, and doses above that made glucose spike. Candidate explanations include ketone-triggered insulin release, better insulin sensitivity (Richard Veech's view) and a shift in the liver's redox balance. Attia says a talk with Stephen Phinney convinced him nobody fully knows the answer.

• 09

  Salts and esters differ in chemistry, and D'Agostino isn't worried about racemic forms.

  Ketone salts bond BHB ionically to sodium, potassium, calcium or magnesium. He calls them 'ketone electrolyte formulations' and limits magnesium BHB to about 1–3 grams per dose for digestive tolerance. Esters bond covalently, for example to 1,3-butanediol, which was researched as a spaceflight fuel. He says the D-form is the better fuel, the L-form lingers longer, and both suppress the inflammasome. He has seen no data suggesting racemic products are harmful.

• 10

  His 'press-pulse' idea for managing cancer metabolically is presented as experimental, not as advice.

  Attia frames the question as a thought experiment with a clear caveat: D'Agostino is a PhD researcher, not an oncologist, and is speaking about a loved one who is still receiving standard treatment and losing. The 'press' is continuous metabolic stress: a calorie-restricted ketogenic diet, eating within about six hours, possibly low-dose metformin, and exogenous ketones. The goal is a glucose-to-ketone ratio of 1–2, versus his guess of 25–50 for a typical person. The 'pulse' includes chemotherapy, radiation and HBOT, which he argues may work better in that changed metabolic state.