Metabolic Therapies Enhance Health and Cognitive Function - Episode Hero Image

Metabolic Therapies Enhance Health and Cognitive Function

The Peter Attia Drive · · Listen to Original Episode →
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TL;DR

  • Ketogenic diets can manage drug-resistant epilepsy, with two-thirds of pediatric patients responding therapeutically, and one-third achieving complete seizure control.
  • Exogenous ketone salts offer a practical bridge into ketosis, mitigating the challenging transition by providing electrolytes and avoiding the insulin spikes associated with ketone esters.
  • Hyperbaric oxygen therapy, particularly at 1.5-2 atmospheres, shows potential for improving cognitive function in individuals with past traumatic brain injuries, though rigorous sham-controlled trials are ongoing.
  • The carnivore diet, when practiced with high-fat animal products, functions as an ultimate elimination diet and can induce ketosis, showing therapeutic promise for autoimmune conditions.
  • Ketone esters, while potent, carry risks of liver toxicity and narcotic effects, making them less suitable for general use compared to ketone salts or MCT formulations.
  • Ketogenic therapies are being explored as adjuvant treatments for glioblastoma, aiming to extend survival by creating an energy crisis in cancer cells when combined with targeted drugs.
  • For Alzheimer's disease, ketogenic therapies may offer benefits by suppressing neuroinflammation, improving glucose metabolism, and providing an alternative brain fuel source, especially in cases of glucose hypometabolism.

Deep Dive

Dr. Dom D'Agostino, a neuroscientist, posits that metabolic therapies, particularly ketogenic diets and exogenous ketones, offer significant therapeutic potential across a range of chronic diseases and cognitive enhancements. His research, initially focused on the neurotoxic effects of oxygen for military applications, revealed the profound impact of ketone bodies on brain function and cellular metabolism, leading to applications in epilepsy, neurodegenerative diseases, and even cancer. The core argument is that by manipulating fuel sources--shifting from glucose to ketones--we can fundamentally alter physiology to combat disease and enhance performance, though the optimal methods for achieving and leveraging ketosis are complex and context-dependent.

D'Agostino outlines nutritional ketosis as a state achieved through carbohydrate restriction, with a blood beta-hydroxybutyrate (BHB) level above 0.5 millimolar serving as a clinical marker. Historically, ketogenic diets, first used to manage epilepsy when drugs failed, have demonstrated remarkable efficacy, with two-thirds of pediatric epilepsy patients responding and a significant portion experiencing complete seizure control. This success, he argues, stems from the ketogenic diet's ability to profoundly change physiology, biochemistry, and neuropharmacology, offering benefits unmatched by other dietary approaches. While weight loss is a common application, D'Agostino emphasizes that the diet's true magic lies in its metabolic and neurochemical effects, including reducing inflammation and enhancing brain resilience. He cautions against common mistakes, such as insufficient tracking of macronutrients and calories, and advocates for a personalized approach, particularly concerning protein intake, which he believes is often underestimated, especially for athletes and those seeking to preserve muscle mass. The carnivore diet is presented as an extreme form of elimination diet that can induce ketosis and may be therapeutically beneficial for autoimmune conditions, functioning as a very strict ketogenic variant.

The field of exogenous ketones has evolved significantly, with D'Agostino highlighting the progression from early, potentially toxic compounds like 1,3-butanediol to more refined ketone salts and esters. He explains that while these supplements can rapidly elevate ketone levels, their application requires careful consideration of formulation and dosage to avoid negative side effects like insulin spikes or energy toxicity. Ketone salts, in particular, offer advantages by providing electrolytes and delaying gastric absorption, thus mitigating the risk of insulin-induced hypoglycemia and adverse GI effects often associated with ketone esters. The racemic mixture of D- and L-BHB found in some supplements is also discussed, with L-BHB potentially offering unique signaling benefits and prolonged ketone elevation, complementing the direct energetic contribution of D-BHB.

D'Agostino sees significant future applications for ketogenic therapies in oncology and neurodegenerative diseases. For glioblastoma, he proposes a framework where ketogenic diets, aiming for a glucose-ketone index (GKI) of 1-4, serve as an adjuvant to standard care, creating an energy crisis for cancer cells and augmenting the efficacy of other treatments. While acknowledging the current lack of definitive randomized controlled trials (RCTs) demonstrating cures, he highlights ongoing research and the potential for significant survival extension and improved quality of life. For Alzheimer's disease and other dementias, the ketogenic approach addresses glucose hypometabolism, a hallmark of these conditions, and suppresses neuroinflammation. He emphasizes that while the exact mechanisms are still being elucidated, ketogenic therapies appear to improve brain energy metabolism and reduce inflammation, offering a potentially more accessible and less burdensome intervention than current pharmaceutical options. He also discusses the role of hyperbaric oxygen therapy (HBOT) for traumatic brain injury (TBI) and cognitive function, noting promising but often methodologically challenged research, and suggests that while not FDA-approved for these indications, HBOT may offer potential benefits, particularly in acute settings, though rigorous trials are still needed.

Action Items

  • Track 3-5 key metabolic biomarkers (e.g., BHB, glucose, lipids) weekly for 4 weeks to establish personal baseline and response to dietary changes.
  • Audit personal carbohydrate intake, identifying 5-10 hidden sources contributing to unexpected glucose spikes.
  • Implement a structured 4-6 week transition plan for dietary changes, incorporating electrolyte supplementation to mitigate potential side effects.
  • Evaluate personal protein needs by calculating intake against lean body mass and activity level, aiming for 1.0-1.2 grams per pound of body weight.
  • Measure cognitive function and energy levels daily for 2 weeks when incorporating exogenous ketones to identify optimal timing and dosage.

Related Episodes

Key Quotes

"the ketogenic diet works for many different seizure disorders when drugs fail so i was like oh i can get nutrition back although i was gravitating towards a tenure track position and everybody told me this is like the dumbest thing to do you can't get nih funding with ketogenic nobody heard of the ketogenic diet and what year was this this is around 2005 i started tinkering with ketones but 2007 i started writing grants and then i hit on a grant in 2008 postdoctoral grant"

This quote highlights the initial skepticism and challenges faced by Dr. D'Agostino when pursuing research on the ketogenic diet, particularly in contrast to conventional academic paths and funding opportunities. It demonstrates his early commitment to exploring this area despite external doubts.

"so the grants that i had were literally called investigating the cellular and molecular mechanisms of cns oxygen toxicity and they gave me unlike the nih they gave me i had a lot of tools to play with that were really expensive that we got through what's called a dod durap grant and that bought chambers and microscopes and electrophysiology equipment it allowed me to tinker in the lab and in the process of tinkering we just had some serendipitous discoveries with the cancer things and then just fundamental effects that happen in cells under high pressure oxygen nitrogen helium different gases very basic"

Dr. D'Agostino explains how military funding, specifically through the DOD DURIP grant, provided him with extensive resources for his research on CNS oxygen toxicity. This funding enabled him to acquire specialized equipment and conduct fundamental research, which unexpectedly led to discoveries related to cancer and cellular responses to extreme environments.

"so clinically a modified version of the ketogenic diet is actually being gravitated more towards even in pediatric epilepsy so we're learning that protein is really important and it was underappreciated i guess in the early ketogenic diets in the context of sports it's extremely important and we can talk about that but still it remains that the ketogenic diet is the most scientifically researched diet that has an objective biomarker that defines the physiological state of being in the diet and that's a beta hydroxybutyrate above 0 5 millimoles per liter so that's clinical ketosis"

This passage defines clinical ketosis, establishing a measurable biomarker (beta-hydroxybutyrate above 0.5 mmol/L) and emphasizing the evolving understanding of the ketogenic diet. Dr. D'Agostino notes the shift towards modified versions that incorporate adequate protein, which was previously underappreciated, and highlights its status as a scientifically researched diet.

"so i view unlike many people out there i view a ketogenic diet as a prescription metabolic therapy so that's the world that i come from there's clinical keto and then there's internet keto and which a lot of people are following a low carb diet which has a plethora of metabolic benefits just have to be up on your blood work and you have to be very vigilant with tracking your biomarkers but a clinical ketogenic diet is typically done with consulting or advice or even following the framework for example a lot of books out there by eric kossoff if you have cancer miriam kalamian has a guide ketogenic diet for cancer books that are out there that tell you step by step on how to do it"

Dr. D'Agostino distinguishes between "clinical keto" and "internet keto," framing the former as a prescribed metabolic therapy requiring professional guidance and structured approaches, often detailed in specialized books. He contrasts this with general low-carb diets, emphasizing the need for vigilance with biomarkers and blood work for clinical applications.

"so the idea is to have monovalent and divalent cations you can spread the beta hydroxybutyrate out to create like a quad salt was the idea back in 2011 so reaching out to patrick it wasn't in the cas database no one had thought about it you couldn't buy it so we had to make it and then we made the calcium and the magnesium and through time basically we settled on a ratio of sodium potassium to calcium similar to element so they're kind of ahead of it but element is sodium chloride so keto start or from audacious nutrition is sodium beta hydroxybutyrate and the calcium and it's got a spread of electrolytes that are similar so you're giving electrolytes and also giving ketones and that's really important when you start a ketogenic diet because you're replenishing the electrolytes that you are spilling out more through a natriuretic effect especially the sodium and also there's an energetic gap in the brain when you start a ketogenic diet where you have an energetic need for the increasing ketones"

This quote details the development of ketone salts, explaining the concept of combining beta-hydroxybutyrate with various cations (sodium, potassium, calcium, magnesium) to create electrolyte-rich supplements. Dr. D'Agostino highlights the novelty of this approach in 2011 and its importance in bridging the energetic gap and replenishing electrolytes during the initial stages of a ketogenic diet.

"so the gist of that for ketone metabolic therapy for cancer management specifically glioblastoma but we think similar reviews can be written for other types of cancers that are specifically that are highly glycolytic and have the warburg effect so really hot on an fdg pet scan so above 2 5 suvs like on a pet scan would define it as hyper glycolytic achieve and maintain a glucose ketone index of one to four so that's the millimolar concentration of glucose over ketones so if your glucose was four which is relatively normal and your ketone levels were one you're at the entry of that zone where i'm at now so that gives me a gki of four standard american diet produces of like a gki of 50 40 or 50 so simply the guidelines are one to two but i think that's too strict"

Dr. D'Agostino outlines the framework for using ketone metabolic therapy in cancer management, particularly for glioblastoma and other highly glycolytic cancers. He defines the target Glucose Ketone Index (GKI) of 1-4, contrasting it with the higher GKI typically seen with a standard American diet, and suggests that current guidelines might be too restrictive.

Resources

External Resources

Books

  • "Ketogenic Diet for Cancer" by Miriam Kalamian - Mentioned as a guide for implementing a ketogenic diet for cancer management.
  • "The Ketogenic Diet" by Eric Kossoff - Mentioned as a guide for implementing a ketogenic diet.

Articles & Papers

  • "Ketone Metabolic Therapy Framework for Glioblastoma" (Nature Medicine) - Mentioned as a comprehensive framework for using ketogenic therapy in glioblastoma treatment.

People

  • Dom D'Agostino, Ph.D. - Guest on the podcast, neuroscientist and professor at the forefront of metabolic therapies.
  • Peter Attia - Host of the podcast, focused on translating longevity science.
  • Ken Ford - Mentioned as the person who connected Peter Attia and Dom D'Agostino.
  • Dr. J.D. (mentor to Dom D'Agostino) - Mentioned in relation to historical research and a lab that is like a museum.
  • Fred Bear - French physiologist who conducted seminal studies on oxygen over 100 years ago.
  • Dr. Frank Butler - Mentioned in relation to the Navy and studies on oxygen toxicity, nitrogen narcosis, and high pressure nervous syndrome.
  • Claude Piantadosi - Mentioned in relation to the Navy and studies on oxygen toxicity, nitrogen narcosis, and high pressure nervous syndrome.
  • Richard Moon - Mentioned in relation to the Navy and studies on oxygen toxicity, nitrogen narcosis, and high pressure nervous syndrome.
  • Dr. George Cahill - Conducted seminal studies on water-only fasts.
  • Dr. Wilderer - Mentioned in relation to early work on ketogenic diets at the Mayo Clinic.
  • Dr. Allison Hall - Conducted a study on people transitioning to a low-carb ketogenic diet.
  • Dr. Donald Layman - Mentioned in relation to research on protein intake.
  • Dr. Stu Phillips - Mentioned in relation to research on protein intake.
  • Dr. Henri Bruningrabber - Mentioned in relation to pioneering work on ketone esters.
  • Dr. Richard Veech - Late mentor to Dom D'Agostino, pioneered ketone ester research.
  • Dr. Jung Roe - Colleague of Dom D'Agostino who suggested looking at acetoacetate.
  • Dr. Brianna Stubbs - Conducted work on D- and L-beta-hydroxybutyrate.
  • Dr. Guido Frank - Expert in eating disorders, running a study on anorexia.
  • Dr. Diana Rancourt - Expert in eating disorders at the University of South Florida.
  • Jan and David Bazuki - Funders of studies on severe psychiatric disorders.
  • Dr. Thomas Seyfried - Senior author of a review on ketone metabolic therapy for glioblastoma.
  • Dr. Jethro Hugh - Conducted a study at UCLA on ketogenic therapy for glioblastoma.
  • Dr. George Brooks - Discussed lactate as an alternative brain fuel.
  • Dr. Mary Newport - Saw improvements in her husband with coconut oil and MCT oil for Alzheimer's.
  • Dr. Theodore Van Itallie - Mentioned in relation to early work on ketones.
  • Dr. Dale Bredesen - Spearheading comprehensive approaches to Alzheimer's.
  • Dr. Stephen Cunnane - Worked on MCTs and other ketogenic agents for Alzheimer's.
  • Dr. Joe DeTuri - Runs a facility at the University of South Florida studying hyperbaric oxygen.

Organizations & Institutions

  • Office of Navy Research (ONR) - Funded Dom D'Agostino's postdoctoral research on CNS oxygen toxicity.
  • Department of Defense (DoD) - Funded research related to CNS oxygen toxicity.
  • National Institutes of Health (NIH) - Mentioned in contrast to military funding for ketogenic diet research.
  • Naval Sea Command (NAVSEA) - Involved in human studies related to naval operations.
  • Mayo Clinic - Conducted early work on ketogenic diets in the 1920s.
  • Moffitt Cancer Center - Colleagues are interested in glucose, ketone, and lactate monitoring for cancer.
  • Buck Institute - Holds patents on L-beta-hydroxybutyrate.
  • University of San Francisco (UCSF) - Where Dr. Guido Frank is based.
  • University of South Florida (USF) - Where Dom D'Agostino works and where a hyperbaric oxygen trial is being conducted.
  • Ohio State University - Funding studies on psychiatric disorders.
  • Stanford - Funding studies on psychiatric disorders.
  • Oxford - Funding studies on psychiatric disorders.
  • Stony Brook - Funding studies on psychiatric disorders.
  • UCSD - Funding studies on psychiatric disorders.
  • UCLA - Funding studies on psychiatric disorders.
  • University of Edinburgh - Funding studies on psychiatric disorders.
  • Aviv Clinic - Treats patients with hyperbaric oxygen therapy.
  • Clearwater, Florida - Location of the Metabolic Health Summit.

Tools & Software

  • Cardio Check Meter - Used for checking ketone levels.
  • Abbott Precision Extra - Used for checking ketone levels.
  • Keto Mojo - Device that measures glucose and ketone levels.
  • Carbon App - Used for tracking food intake and macronutrients.
  • Biosense Device - Breath acetone meter correlated with seizure control.
  • Keto Air - Breath acetone meter.
  • Continuous Ketone Monitor (CKM) - Device for tracking ketone levels.
  • Levels Health - Company Dom D'Agostino advises for, related to CGM.
  • Metapy (METPY) - App and program for metabolic psychiatry.
  • RF Sugar - Company that sold allulose.

Websites & Online Resources

  • peterattiamd.com - Peter Attia's website, offering show notes, membership, and newsletter.
  • clinicaltrials.gov - Database for registered clinical trials.
  • PubMed - Database for peer-reviewed publications.
  • Keto Nutrition - Dom D'Agostino's informational website.

Podcasts & Audio

  • The Peter Attia Drive - Podcast hosted by Peter Attia.
  • Metabolic Link Podcast - Podcast associated with the Metabolic Health Initiative.

Other Resources

  • Ketogenic Diet - A diet primarily high in fat, moderate in protein, and low in carbohydrates.
  • Nutritional Ketosis - Achieving ketosis through diet.
  • Supplemental Ketosis (Exogenous Ketones) - Achieving ketosis through supplements.
  • Alcoholic Ketoacidosis - A form of ketoacidosis caused by excessive alcohol consumption.
  • Diabetic Ketoacidosis - A serious complication of diabetes.
  • Beta-hydroxybutyrate (BHB) - A ketone body produced by the liver.
  • Acetoacetate - A ketone body produced by the liver.
  • Acetone - A ketone body.
  • 1,3-Butanediol - An alcohol that is ketogenic.
  • Ketone Salts - Supplements that combine beta-hydroxybutyrate with a mineral cation.
  • Ketone Esters - Supplements where beta-hydroxybutyrate is covalently bonded to another molecule.
  • Glycerol Beta-hydroxybutyrate Ester - A type of ketone ester.
  • Acetoacetate Diester - A type of ketone ester.
  • Monoester of Beta-hydroxybutyrate - A type of ketone ester.
  • Racemic Ketones - A mixture of D- and L-beta-hydroxybutyrate.
  • D-beta-hydroxybutyrate - The naturally occurring form of beta-hydroxybutyrate in the body.
  • L-beta-hydroxybutyrate - The mirror image of D-beta-hydroxybutyrate.
  • NAD (Nicotinamide Adenine Dinucleotide) - A coenzyme involved in cellular metabolism.
  • NMN (Nicotinamide Mononucleotide) - A precursor to NAD.
  • NR (Nicotinamide Riboside) - A precursor to NAD.
  • GPR109A Receptor - A receptor that ketones can interact with.
  • NLRP3 Inflammasome - An inflammatory pathway that ketones can suppress.
  • Epigenetic Effects - Changes in gene expression that do not involve alterations to the underlying DNA sequence.
  • Reductive Stress - An imbalance in cellular redox state.
  • NAD+/NADH Ratio - A measure of cellular redox state.
  • Gluconeogenesis - The metabolic process by which organisms produce glucose from non-carbohydrate sources.
  • Glycogenolysis - The breakdown of glycogen to glucose.
  • Beta Oxidation - The process of breaking down fatty acids.
  • Glioblastoma - A type of aggressive brain tumor.
  • Warburg Effect - The phenomenon where cancer cells preferentially metabolize glucose through glycolysis.
  • FDG PET Scan - A medical imaging technique that uses a radioactive tracer to measure glucose metabolism.
  • SUV (Standardized Uptake Value) - A metric used in PET scans to quantify tracer uptake.
  • Glucose Ketone Index (GKI) - A ratio of blood glucose to blood ketone levels.
  • Metformin - A drug used to treat type 2 diabetes, also studied for its potential anti-cancer effects.
  • Loonidamine - A hexokinase inhibitor.
  • Three Bromopyruvate - A hexokinase inhibitor.
  • Two Deoxyglucose - A hexokinase inhibitor.
  • SGLT2 Inhibitor - A class of drugs used to treat type 2 diabetes.
  • Glutamine - An amino acid that can be used as a fuel source by cancer cells.
  • Glutaminase - An enzyme that breaks down glutamine.
  • Sodium Phenylbutyrate - A drug that can bind to glutamine.
  • Glycerol Phenylbutyrate - A drug that can bind to glutamine.
  • HDAC Inhibitor - A class of drugs that inhibit histone deacetylase enzymes.
  • EGCG (Epigallocatechin gallate) - A compound found in green tea.
  • Curcumin - A compound found in turmeric.
  • Quercetin - A flavonoid found in many plants.
  • Car T Therapy - A type of cancer treatment that uses a patient's own immune cells.
  • Checkpoint Inhibitors (PD-1, CTLA-4) - Drugs that help the immune system fight cancer.
  • Alzheimer's Disease - A neurodegenerative disease that causes dementia.
  • Dementia - A general term for a decline in mental ability severe enough to interfere with daily life.
  • Mild Cognitive Impairment (MCI) - A stage between normal aging and dementia.
  • Amyloid - A protein that can accumulate in the brain and is associated with Alzheimer's disease.
  • Tau - A protein that can accumulate in the brain and is associated with Alzheimer's disease.
  • Neuroinflammation - Inflammation in the brain.
  • ApoE4 Carrier - A genetic variant that increases the risk of Alzheimer's disease.
  • PSEN1, PSEN2, APP genes - Genes

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