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

Episode Summary

Executive Summary: Peter Attia interviews Dominic D’Agostino on ketosis, exogenous ketones, hyperbaric oxygen, and cancer metabolism. The conversation spans Dom’s neuroscience and diving-physiology background, his self-experiments, the biochemistry of ketones, and a proposed “metabolic oncologist” framework using ketogenic strategies plus selected therapies to stress tumors while protecting healthy tissue.

Main Topics: Dom D’Agostino’s scientific path and hyperbaric microscopy (Priority: 5/5): Dom explains his neuroscience PhD, postdoctoral work on hyperbaric atomic force microscopy, and how imaging cells under pressure led him into oxygen toxicity, mitochondrial biology, and cancer metabolism. Warburg effect and cancer metabolism (Priority: 5/5): The discussion revisits the Warburg effect, arguing that many cancers rely on glycolysis despite oxygen availability, and that mitochondrial dysfunction, redox signaling, and metabolic reprogramming are central to tumor biology. Ketosis, starvation physiology, and brain fuel partitioning (Priority: 5/5): They review Cahill’s starvation studies, how the brain shifts from glucose to ketones, and why ketones can preserve brain function during fasting, hypoglycemia, and metabolic stress. Exogenous ketones: salts, esters, stereochemistry, and MCTs (Priority: 5/5): A detailed breakdown of ketone salts vs esters, D vs L beta-hydroxybutyrate, acetoacetate, 1,3-butanediol, and medium-chain triglycerides, including tolerability, potency, and practical use. Ketones, seizures, and oxygen toxicity (Priority: 4/5): Dom describes how ketones may protect against CNS oxygen toxicity and seizures, including diving-related risk, hyperbaric oxygen effects, and the role of glutamate/GABA balance and oxidative stress. Metabolic oncology playbook (Priority: 5/5): The pair outline a conceptual cancer strategy: continuous ‘press’ metabolic therapy (ketogenic diet, fasting, metformin, exogenous ketones) plus ‘pulse’ therapies (hyperbaric oxygen, IV vitamin C, glycolytic inhibitors) to sensitize tumors. Self-experimentation and translational implications (Priority: 4/5): Both speakers emphasize N-of-1 experimentation, the need for rigorous trials, and the potential for metabolic therapies in epilepsy, traumatic brain injury, cancer, and performance settings.

Key Arguments: Ketosis is not just an alternative fuel state; beta-hydroxybutyrate also acts as a signaling molecule with epigenetic effects. Cancer cells often depend on glycolysis and can be selectively stressed by restricting fermentable fuels while preserving normal tissue with ketones. Hyperbaric oxygen can be therapeutic in some contexts because it increases dissolved oxygen in plasma and can amplify oxidative stress in tumors or injured tissue. Exogenous ketones can raise blood ketones without strict dietary ketosis, but their effects depend on formulation, stereochemistry, and dose. Acetoacetate appears important for anti-seizure effects; pure beta-hydroxybutyrate alone may be insufficient in some models. MCTs are a practical way to raise ketones and may have drug-like properties beyond ketone production. A combined metabolic approach may improve the efficacy of standard cancer therapies by lowering glucose availability and altering tumor redox state. Self-experimentation helped generate hypotheses, but Dom repeatedly stresses that these approaches are not medical advice and require proper clinical study.

Data Points: Podcast length: Nearly 3 hours - Attia notes the episode is long and highly technical. Cahill fast duration: 40 days - George Cahill’s starvation study on brain fuel metabolism. Glucose during fast: ~3 mmol/L (~55 mg/dL) - Maintained after about day 7 of the fast. Ketone contribution to brain energy: ~60% from beta-hydroxybutyrate - Approximate brain fuel partitioning after prolonged fasting. Acetoacetate contribution to brain energy: ~10% - Estimated contribution in Cahill’s fasting studies. Glucose contribution to brain energy: ~30% - Remaining brain energy after adaptation to fasting. Insulin during fasting studies: Very low / near rock bottom - Observed by day 7 in Cahill’s subjects. Insulin challenge glucose: ~1 mmol/L (<20 mg/dL) - Insulin infusion in fasted subjects with maintained ketones and minimal symptoms. Ketone levels in classical ketogenic diet: ~2 to 2.5 mmol/L - Dom’s personal measurements on a classical ketogenic diet. Ketone levels in long fast: ~4 to 5 mmol/L - Dom’s personal measurements after a seven-day fast. Glucose-ketone index target: 1 to 2 - Proposed target in the metabolic oncology ‘press’ protocol. Hyperbaric oxygen exposure in cell work: 0.95 ATA oxygen and up to 3.25 ATA oxygen - Conditions under which cancer cells showed marked oxidative stress and damage. Oxygen toxicity dive example: 50 feet seawater for 10 minutes - Attia and Dom discuss seizure risk on oxygen rebreathers. Ketone ester effect on oxygen toxicity: ~600% increase in resistance - Dom cites ketone esters increasing resistance to oxygen toxicity. Hyperbaric oxygen therapy frequency: 3 times per week - Suggested frequency in the cancer pulse protocol. Hyperbaric oxygen therapy pressure: ~2.5 ATA for 60 minutes - Suggested tumor-directed protocol, with lower starting pressure for seizure-prone cases. Vitamin C dose: 25 to 100 grams IV - Discussed as a pro-oxidant adjunct in cancer therapy. Metformin dose range: 500 to 2000 mg/day - Suggested low-dose metabolic adjunct. 2-deoxyglucose dose: ~25 mg/kg - Discussed as a potentially therapeutic and safer range in epilepsy/cancer contexts. Ketone salt market scale: Millions of doses per month - Dom notes widespread commercial use of racemic ketone salts. NEMO mission duration: 10 days in saturation - Dom’s NASA underwater mission and metabolic self-experimentation. Decompression time: 18 to 19 hours - Time required to return from saturation habitat. Weight change on NEMO: ~9 lb lost - Dom reports losing weight during the mission. Testosterone change: ~25% decrease - Observed during the underwater mission. Sleep change: ~2.5 hours deep sleep/night - Dom reports more deep sleep than usual during the mission. Breast cancer case anecdote: 6 years on ketogenic diet - Attia cites a patient surviving on ketogenic therapy alongside clinical trial care.

Pivotal Quotes: "“The ketogenic diet worked when drugs failed, you know, suggesting it was working through a different mechanism or many mechanisms kind of in synchrony.”" — Dominic D’Agostino: Explaining why ketosis became compelling as an anti-seizure strategy. "“The cancer cells would die.”" — Dominic D’Agostino: Describing experiments where ketones plus low glucose selectively harmed cancer cells. "“I think the biggest thing to do is to augment your brain energy metabolism, to burn energy more efficiently.”" — Dominic D’Agostino: Summarizing his view on protecting the brain in oxygen toxicity and injury.

Implications: The episode frames ketosis as both a fuel strategy and a signaling intervention, with potential relevance to epilepsy, diving safety, TBI, and cancer. It also argues for a future field of metabolic oncology, but emphasizes rigorous clinical validation before use.