Key Moments
#05 - Dom D’Agostino, Ph.D.: ketosis, n=1, exogenous ketones, HBOT, seizures, and cancer
Peter Attia MDKey Moments
Dom D'Agostino on ketosis, exogenous ketones, HBOT, and their use in seizures, TBI, and cancer.
Key Insights
Ketones, particularly BHB and acetoacetate, serve as an alternative brain fuel, crucial in states of low glucose and offering neuroprotective qualities.
Hyperbaric Oxygen Therapy (HBOT) can exacerbate oxidative stress in cancer cells, due to their unique metabolic properties and defects in mitochondria, making it a targeted therapeutic approach when combined with nutritional ketosis.
Exogenous ketones (salts and esters) can elevate blood ketone levels, offering a way to induce therapeutic ketosis without strict dietary adherence, with potential benefits in seizure management and metabolic health.
The 'Press-Pulse' strategy in cancer therapy combines continuous metabolic stress (dietary ketosis, metformin) with intermittent pulse stressors (HBOT, IV vitamin C, specific glycolytic inhibitors) to target cancer cells.
Metabolic therapies, like the ketogenic diet, act as epigenetic drivers, influencing gene expression beyond just energy production, with implications for genetic disorders like Kabuki syndrome.
Antioxidants may hinder the efficacy of some cancer treatments that rely on increasing oxidative stress to kill cancer cells, suggesting a nuanced approach in oncology.
INTRODUCTION TO DR. DOM D'AGOSTINO'S RESEARCH
Dr. Dom D'Agostino, a professor with a Ph.D. in neuroscience, is a leading expert on ketosis and its applications. His journey into this field began during his postdoctoral fellowship, where he developed hyperbaric atomic force microscopy to study cellular function in extreme environments. This unique technology allowed him to observe cancer cells' peculiar behavior under hyperbaric oxygen, sparking his interest in metabolic cancer therapies and the neuroprotective effects of ketones.
OXYGEN TOXICITY SEIZURES AND HYPERBARIC OXYGEN THERAPY (HBOT)
D'Agostino's initial research focused on understanding oxygen toxicity seizures, a risk for Navy SEAL divers using rebreathers. He discovered that high oxygen levels create oxidative stress, leading to neuronal hyperexcitability and seizures, which can be mitigated by ketosis. HBOT, while beneficial for conditions like wound healing and carbon monoxide poisoning, also carries seizure risks. Ketone esters significantly increase resistance to oxygen toxicity, suggesting that therapeutic ketosis could make HBOT safer and more effective across its 15 FDA-approved applications.
THE WARBURG EFFECT AND CANCER METABOLISM
D'Agostino discusses the Warburg Effect, a phenomenon where cancer cells predominantly use glycolysis for energy, even in the presence of oxygen. His observations showed that cancer cells, despite having numerous mitochondria, generated excessive reactive oxygen species (ROS) under hyperbaric oxygen, leading to cell death. This contradicted the notion of cancer cells being strictly anaerobic, highlighting their metabolic flexibility and vulnerability to metabolic stress, especially when their antioxidant capacity is overwhelmed.
KETONES AS ALTERNATIVE FUEL AND SIGNALING MOLECULES
Inspired by George Cahill's starvation studies, D'Agostino delved into ketones' role in brain metabolism. Cahill's work showed that after prolonged fasting, the brain could derive 60-70% of its energy from beta-hydroxybutyrate (BHB) and acetoacetate, significantly reducing its reliance on glucose. Beyond providing an alternative fuel source, D'Agostino emphasizes ketones' critical signaling properties, such as their role as histone deacetylase (HDAC) inhibitors, which influence gene expression and epigenetic regulation, a 'mind-blowing' discovery with significant therapeutic implications.
NUTRITIONAL KETOSIS AND MCT OIL
D'Agostino's personal n=1 experiments with the classical ketogenic diet (4:1 fat-to-protein/carb ratio) initially struggled to achieve high ketone levels. The incorporation of MCT (Medium-Chain Triglyceride) oil, particularly C8 (caprylic acid), significantly boosted ketone production. MCTs are rapidly metabolized in the liver to produce ketones and can even cross the blood-brain barrier directly. He highlights that MCTs are a 'poor man's ketone ester' — a more accessible way to raise ketone levels, even on a high-carb diet, albeit with potential gastrointestinal tolerance issues at higher doses.
EXOGENOUS KETONES: SALTS, ESTERS, AND ENANTIOMERS
The discussion elaborates on exogenous ketones (EKs), differentiating between ketone salts and esters. Salts, formed by ionic bonds with minerals like sodium or magnesium, provide a palatable way to elevate ketones. Esters, involving a covalent bond (e.g., BHB with 1,3-butanediol), are more potent but often have an unpalatable taste. D'Agostino's research suggests that while D-BHB is the predominant physiological form and offers metabolic benefits, acetoacetate and some L-BHB (often present in racemic salts) may contribute unique anti-seizure and anti-inflammatory effects, making the balance of ketone bodies important for therapeutic efficacy.
GLUCOSE-KETONE INDEX (GKI) AND INTERMITTENT FASTING
A critical metric in metabolic therapy is the Glucose Ketone Index (GKI), aiming for a ratio of 1:2 or better (glucose to ketones, measured in millimolars). This significantly restricts fermentable fuels for cancer cells and suppresses insulin. Achieving this GKI is supported by a 'supplemented ketogenic intermittent fasting' approach, where eating is restricted to a 6-hour window, and exogenous ketones can be used during fasting to further lower glucose and raise ketone levels. This strategy is part of a 'Press-Pulse' protocol for cancer, creating continuous metabolic stress.
THE PRESS-PULSE PROTOCOL FOR CANCER THERAPY
D'Agostino outlines a 'Press-Pulse' strategy for cancer, particularly for aggressive forms like glioblastoma. The 'Press' involves continuous metabolic stress: a calorie-restricted ketogenic diet, intermittent fasting, and low-dose metformin, aiming for a GKI of 1:2 or better. The 'Pulse' components deliver intermittent, targeted insults: HBOT, IV vitamin C (as a pro-oxidant at high doses), and specific glycolytic inhibitors like 2-deoxyglucose (2DG) or dichloroacetate (DCA). The goal is to make cancer cells selectively vulnerable to oxidative stress and to disrupt their aberrant metabolism, while preserving healthy cells.
HYPERBARIC OXYGEN THERAPY (HBOT) IN CANCER
HBOT, as a pulse therapy, works by reversing tumor hypoxia, a state where cancer cells thrive and promote angiogenesis. By driving oxygen into the plasma (rather than just hemoglobin), HBOT allows oxygen to reach poorly vascularized tumor regions. This hyper-oxygenation of damaged mitochondria in tumor cells, combined with the presence of free iron, leads to a massive production of reactive oxygen species (ROS), triggering apoptosis and necrosis. Importantly, this pro-oxidant effect selectively harms cancer cells while sparing healthy tissue with normal metabolism.
IV VITAMIN C AND GLYCOLYTIC INHIBITORS
Intravenous (IV) vitamin C, at gram doses, acts as a pro-oxidant, generating more oxidative stress (via the Fenton reaction) that specifically targets cancer cells. This is distinct from its antioxidant effects at lower oral doses. D'Agostino emphasizes avoiding antioxidant supplements during cancer treatment, as they can interfere with therapies (chemo, radiation) that rely on oxidative stress to kill cancer cells. Glycolytic inhibitors like 2DG and DCA further disrupt cancer metabolism by blocking glucose utilization and the pentose phosphate pathway, making cells more vulnerable to oxidative damage.
THE METABOLIC ONCOLOGIST: A NEW PARADIGM
D'Agostino advocates for the emergence of 'metabolic oncologists' alongside surgical, radiation, and medical oncologists. He argues that metabolic interventions can serve as neoadjuvant, concurrent, or adjuvant strategies, enhancing the efficacy of conventional treatments. The goal is to create a metabolic state where the patient's body becomes more resilient and robust, while simultaneously sensitizing cancer cells to targeted destruction. This approach views cancer as a metabolic disease influenced by genetics, emphasizing a comprehensive and individualized approach.
N=1 EXPERIMENTATION AND PHYSIOLOGIC ADAPTATION
Throughout his journey, D'Agostino has engaged in extensive self-experimentation, pushing the boundaries of physiological adaptation. He recounted a 7-day water-only fast where he maintained impressive physical strength (deadlifting 500 lbs) and cognitive function, with glucose levels dropping to 3 millimolar and ketones rising to 4-5 millimolar. This profound metabolic shift highlights the body's resilience when fully keto-adapted, demonstrating the potential for maintaining performance and cognitive function even under austere conditions with limited food availability.
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Common Questions
Dominic D'Agostino, a professor at the University of South Florida with a PhD in neuroscience, is a leading expert on ketosis, including starvation, nutritional, and exogenous ketones. He is well-known for his extensive research and self-experimentation in this field.
Topics
Mentioned in this video
Granted funding to Dominic D'Agostino for developing hyperbaric atomic force microscopy technology.
Mentioned by Attia as an organization they tried to get interested in TBI research.
Pioneered anti-seizure therapy and developed many of the protocols for the ketogenic diet that are still in use today.
Special forces divers who face limitations due to oxygen toxicity seizures, which D'Agostino's research aims to predict and prevent using ketosis strategies.
University where Honoré Brunengraber works as director of the Metabolomics NIH funded core.
Where D'Agostino collaborated with oncologists to publish a paper on the ketogenic diet targeting cancer hallmarks.
Where Adrian Check conducted research on glioblastoma mouse models and the efficacy of nutritional ketosis with radiation.
The institution where Dominic D'Agostino is a professor.
An incredible resource that D'Agostino has helped with educational work, dedicated to the ketogenic diet for epilepsy.
Location where George Cahill's fasting studies were conducted and passed ethics review.
The defense agency that funded research into ketone esters for warfighter performance.
Worked with Johns Hopkins in pioneering anti-seizure therapy, specifically the ketogenic diet.
University where Attia and Ryan Flaherty attempted to get an IRB for muscle biopsy studies.
Mentioned as where Dr. Eric Verdin (V redeemeth) has spoken about ketones as epigenetic regulators.
Conducted research on 1,3-butanediol as a space fuel in the 1950s-70s.
Mentioned in the context of increased awareness and funding for research into traumatic brain injuries and concussions.
Co-sponsor of the Metabolic Health Summit with D'Agostino's lab.
A laser scanning microscope used by D'Agostino to section individual cells and observe mitochondria under varying oxygen and hyperbaric pressure levels.
A scanning probe microscopy technique used by D'Agostino to image living cells and detect subtle changes at the nanoscopic level, particularly in mitochondria and cell membranes under hyperbaric conditions.
D'Agostino's website, maintained for informational purposes, listing podcasts, nutrition consultants, resources (like the Charlie Foundation), a blog, and test results for ketone supplements and ketogenic foods.
Nobel laureate whose student D'Agostino mentioned Dr. Veech was, connecting to fundamental biochemistry.
Scientist who won a Nobel Prize for his observations on cancer cell metabolism, particularly the Warburg effect.
An organic chemist and 'artist' who helped D'Agostino synthesize ketone esters, especially the diaster, crucial for D'Agostino's academic success and research.
Author of the book 'Tripping Over the Truth', which explains reasons for the Warburg effect being largely ignored.
A significant cancer scientist who co-authored a Science paper that offered an explanation for the Warburg effect.
A friend of the speakers who is a Navy SEAL, mentioned in the context of underreported oxygen toxicity seizures among divers.
Mentioned by Attia as one of the most knowledgeable experts on ketosis.
A doctor mentioned for his work with hyperbaric oxygen therapy, specifically in a case where a young girl with severe hypoxic brain injury regenerated brain function.
Author of a book on the classical ketogenic diet and later the modified ketogenic diet, which D'Agostino used to guide his initial self-experimentation.
A researcher with whom Attia had a discussion about whether the anti-seizure properties of the ketogenic diet are due to alternative fuel or glucose reduction.
Creator of Brain Octane, a caprylic triglyceride product.
Director of the Metabolomics NIH funded core at Case Western, who shared the recipe for synthesizing ketone esters with D'Agostino.
A colleague and friend of D'Agostino who demonstrated in a mouse model of glioblastoma that nutritional ketosis combined with radiation therapy significantly increased efficacy, even curing the cancer.
Host of the 'The Drive' podcast, details his personal and professional interactions with Dom D'Agostino, and introduces complex technical topics.
Cancer researcher whose work D'Agostino stumbled upon, speculating on the Warburg effect, and who is a keynote speaker at the Metabolic Health Summit.
A former postdoc with George Cahill and collaborator, mentioned for his work and understanding of insulin sensitivity in the presence of ketones. Also known as Richard L. Veech.
An individual with whom Attia tried to get an IRB at UCSD to do muscle biopsies related to training and MCT upregulation.
Credited with creating an amazing resource at the Charlie Foundation.
Conducted highly influential starvation experiments where subjects fasted for 40 days, revealing insights into brain energy metabolism and ketone body utilization, which motivated D'Agostino's own research.
Professor at the University of South Florida with a PhD in neuroscience, an expert on ketosis including starvation, nutritional, and exogenous ketones, and known for self-experimental research.
Co-authored a book on the classical ketogenic diet with Eric Kossoff.
Host of a podcast where Attia shared an anecdote about consuming D'Agostino's early ketone esters, and mentioned as someone who interviewed Patrick Arnold.
A prominent cancer researcher and keynote speaker at cancer metabolism conferences.
A brand that makes a powdered MCT formula, which D'Agostino found effective for increasing ketone levels.
A device used by D'Agostino to collect heart rate variability data during his NASA NEEMO mission.
A device for measuring blood beta-hydroxybutyrate levels at home, used by D'Agostino and Attia for personal monitoring.
An example of a pharmaceutical that caused problems due to using the wrong enantiomer.
A wearable device used by D'Agostino for sleep tracking during his NASA NEEMO mission.
A home assay kit device that measures blood beta-hydroxybutyrate, used and validated by D'Agostino's lab.
A glycolytic inhibitor described as being 'the ketogenic diet in a drug' due to its ability to inhibit glycolysis. It is being studied in phase 2 cancer trials and epilepsy. It inhibits the pentose phosphate pathway, making cancer cells more vulnerable to oxidative stress.
An example of a pharmaceutical that caused problems due to using the wrong enantiomer.
A powerful glycolytic inhibitor considered for use in pulse protocols in metabolic cancer therapy.
IV fluid solution mentioned in the context of racemic compounds; D'Agostino notes it used to be racemic and now may be available in both D and L forms.
A chemotherapy drug mentioned in conjunction with radiation, where the effectiveness was greatly increased in a GBM mouse model when combined with nutritional ketosis.
A small molecule drug that D'Agostino's lab has worked with to inhibit the pyruvate dehydrogenase complex, used normally for lactic acidosis and also as a potential cancer therapeutic.
Mentioned as a drug that is racemic.
A drug used in many studies in D'Agostino's lab for its effects on glucose levels, insulin, and amp-kinase activation, inhibiting gluconeogenesis and mildly inhibiting mitochondria complex I, and is also considered a cheap drug for glucose ketone index maintenance in cancer.
An extra-kinase 2 inhibitor mentioned as a powerful drug for pulse protocols in metabolic cancer therapy.
Mentioned as a common pharmaceutical that exists in racemic form.
A specific human glioblastoma cell line used in D'Agostino's research to study reactive oxygen species and oxygen toxicity seizures, which showed excess free radical production under hyperbaric oxygen.
A highly aggressive and uniformly fatal brain cancer, considered one of the worst cancers. D'Agostino discusses metabolic strategies to treat it, including ketogenic diet and hyperbaric oxygen therapy.
Described as insufficient mitochondrial oxidative phosphorylation with compensatory fermentation (glycolysis and substrate-level phosphorylation), a characteristic of most cancer cells where they disproportionately generate ATP anaerobically even in the presence of oxygen.
A metabolic strategy for cancer treatment developed by D'Agostino's lab, aiming to continuously stress cancer cells metabolically ('press' with calorie restriction, ketogenic diet, metformin) and then intermittently apply 'pulse' protocols (HBOT, IV Vitamin C, specific glycolytic inhibitors) to kill vulnerable cells.
Used by D'Agostino's team to look at cognitive psych parameters during the NASA NEEMO mission.
A medical treatment involving breathing oxygen in a pressurized chamber, discussed for its applications in wound healing, decompression sickness, carbon monoxide poisoning, radiation necrosis, and traumatic brain injury, with benefits potentially augmented by ketosis but also risks of oxygen toxicity seizures.
D'Agostino expresses interest in testing low levels of hyperbaric oxygen therapy combined with ketone esters for TBI, aiming to restore oxygenation, decrease inflammation, and increase energy to salvage neurons.
A form of orally available lactate that D'Agostino was initially interested in for preserving brain energy metabolism in the face of oxidative stress before turning to ketones.
A type of saturated fat, typically C8 and C10, that is rapidly oxidized by the liver and transported directly to the liver, bypassing chylomicrons. It can significantly boost ketone levels and is described as 'the poor man's ketone ester' or 'middle-class man's ketone ester'.
The first exogenous ketone identified clinically and used for rare metabolic disorders. A 'ketone salt' created by an ionic bond between BHB and sodium.
A ketone ester product with R-1,3-butanediol and R-beta-hydroxybutyrate, designed to raise ketone levels effectively. Mentioned as mimicking the body's natural D-enantiomer predominance.
Used as a pulse protocol in D'Agostino's metabolic cancer therapy, given intravenously at high doses (25-100 grams) to act as a pro-oxidant and glucose antagonist, selectively stressing tumor cells.
A medium-chain triglyceride, specifically C8, which is pure and more potent for ketone elevation than a mix of C8/C10. Available as Brain Octane and Captri oil.
A synthetic compound that breaks down completely to beta-hydroxybutyrate, researched by MIT in the 1950s-70s as an alternative energy fuel for spaceflight, and used in ketone ester synthesis.
A journal where D'Agostino published a paper in 2017 with oncologists on how the ketogenic diet targets hallmarks of cancer.
A book mentioned by D'Agostino that summarizes the reasons why the Warburg effect in cancer research was largely overlooked for a long period.
A scientific journal where a paper was published showing that the nlrp3 inflammasome is suppressed by beta-hydroxybutyrate.
A rare genetic disease caused by a gene defect in KMT2D (an acetylase enzyme), which leads to an imbalance in gene expression. D'Agostino's lab found that nutritional ketosis, functioning as a histone deacetylase inhibitor, can rescue the phenotype in mouse models by restoring neuronal density and enhancing learning and memory.
A rare genetic disorder characterized by seizures, for which exogenous ketones are being studied as a potential independent therapy, even on a standard diet.
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