Dr. Dominic D’Agostino — All Things Ketones, How to Protect the Brain and Boost Cognition, Sardine Fasting, Diet Rules, Revisiting Metformin and Melatonin, and More (#825)

Dr. Dominic D’Agostino (@DominicDAgosti2) is a tenured associate professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida Morsani College of Medicine and a Visiting Senior Research Scientist at the Institute for Human and Machine Cognition.

He teaches medical neuroscience, physiology, nutrition, and neuropharmacology, and his research focuses on the development and testing of nutritional strategies and metabolic-based therapies for neurological disorders, cancer, and human performance optimization. His work spans both basic science and human clinical trials.

He has a strong personal interest in environmental medicine and enhancing the safety and resilience of military personnel and astronauts. In this capacity, he served as a research investigator and crew member on NASA’s Extreme Environment Mission Operations. His research has been supported by the Office of Naval Research, the Department of Defense, the National Institutes of Health, private organizations, and nonprofit foundations.

He earned his B.S. in Nutritional Science and Biological Sciences from Rutgers University in 1998, followed by a predoctoral fellowship in Neuroscience and Physiology at Rutgers and the University of Medicine and Dentistry of New Jersey. He then completed postdoctoral training in Neuroscience at Wright State University’s Boonshoft School of Medicine in 2004 and at University of South Florida Morsani College of Medicine in 2006.

Please enjoy!

Listen to the episode on Apple Podcasts, Spotify, Overcast, Podcast Addict, Pocket Casts, Castbox, YouTube Music, Amazon Music, Audible, or on your favorite podcast platform. Watch the conversation on YouTube. The transcript of this episode can be found here. Transcripts of all episodes can be found here.

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SELECTED LINKS FROM THE EPISODE

• Connect with Dr. Dominic D’Agostino:

KetoNutrition.org | Facebook | Twitter | University of South Florida

The transcript of this episode can be found here. Transcripts of all episodes can be found here.

Dr. Dominic D’Agostino’s Past Appearances

• Dom D’Agostino on Fasting, Ketosis, and the End of Cancer | The Tim Ferriss Show #117
• Dom D’Agostino — The Power of the Ketogenic Diet | The Tim Ferriss Show #172
• Dom D’Agostino on Disease Prevention, Cancer, and Living Longer | The Tim Ferriss Show #188

Concepts & Ideas

• APOE3/4 Genotype: A genetic variant where individuals carry one copy each of the APOE3 and APOE4 alleles, associated with moderately increased risk of Alzheimer’s disease compared to APOE3/3 but lower risk than APOE4/4.
• Type 3 Diabetes: A term used to describe Alzheimer’s disease as a form of insulin resistance and insulin deficiency that occurs specifically in the brain, characterized by impaired neuronal glucose metabolism.
• The Four Horsemen of Chronic Disease: The four pillars of chronic disease, according to Dr. Peter Attia.
• Glucose Hypometabolism: A state where the brain’s ability to use glucose for energy is impaired, often occurring more than 10 years before the onset of Alzheimer’s disease symptoms and considered a key feature of neurodegeneration.
• Neuroinflammation: Inflammation of nervous tissue involving activation of microglia and astrocytes, considered a major driver of neurodegenerative diseases including Alzheimer’s, Parkinson’s, and multiple sclerosis.
• Ketogenic Diet: A very low-carbohydrate (typically under 50g per day), high-fat diet originally developed at Mayo Clinic in the 1920s to treat epilepsy, which forces the body to produce ketones for fuel instead of using glucose.
• Mediterranean-Style Low-Carb Diet: A modified version of the traditional Mediterranean diet that reduces carbohydrate intake while emphasizing vegetables, fish, olive oil, nuts, and healthy fats to support weight loss and blood sugar control.
• Exogenous Ketones: Ketone bodies (primarily beta-hydroxybutyrate) that are consumed through nutritional supplements in the form of ketone salts, esters, or precursor compounds, allowing for rapid elevation of blood ketones without dietary restriction.
• Ketone Monoester vs. Diester vs. Salts: Different forms of exogenous ketone supplements where monoesters provide the most efficient ketone elevation, diesters are bonds between two ketone molecules, and salts combine ketones with minerals like sodium or potassium.
• Glucose Ketone Index (GKI): A ratio calculated by dividing blood glucose levels by ketone levels, used as a biomarker for metabolic health and the depth of ketosis, with lower values indicating better metabolic flexibility.
• Fasting and “Sardine Fasting”: Abstaining from food for therapeutic benefits, with “sardine fasting” referring to a modified fasting approach where only sardines are consumed, providing protein while maintaining some benefits of fasting.
• Autophagy: The body’s cellular recycling process of cleaning out damaged organelles and proteins to regenerate newer, healthier cellular components, enhanced during periods of fasting and ketosis.
• Cancer Cachexia: A complex metabolic syndrome characterized by severe loss of muscle mass and body weight, often accompanied by anemia, weakness, and loss of appetite in cancer patients.
• Metabolic Psychiatry: An emerging field that uses metabolic interventions, particularly ketogenic diets and exogenous ketones, to treat mental health conditions by addressing underlying metabolic dysfunction in the brain.
• NLRP3 Inflammasome: A multiprotein complex in immune cells that acts as a cellular sensor and triggers inflammatory responses, playing a crucial role in innate immunity and implicated in various neurodegenerative diseases.
• Metabolic Control of Epigenetic Regulation: The concept that metabolites like beta-hydroxybutyrate can directly influence gene expression by acting as signaling molecules and histone deacetylase inhibitors, affecting cellular function and health.
• Redox Stress: An imbalance in the cellular ratio of NAD+ to NADH that can impair mitochondrial function and energy production, often associated with aging and metabolic dysfunction.
• Hyperbaric Oxygen Therapy (HBOT): A medical treatment involving breathing pure oxygen in a pressurized chamber at 1.5 to 3 times normal atmospheric pressure, used to enhance healing and treat various conditions including wound healing and carbon monoxide poisoning.
• Lipid Energy Model: A metabolic model explaining how LDL cholesterol and ApoB particles can be elevated on low-carbohydrate diets as they function as transport vehicles for mobilized fatty acids used for energy production.
• SARM (Selective Androgen Receptor Modulator): A class of therapeutic compounds designed to selectively bind to androgen receptors in specific tissues, potentially offering the muscle-building benefits of anabolic steroids with reduced androgenic side effects.

Substances & Drugs

• Beta-Hydroxybutyrate (BHB): The primary ketone body produced during fat metabolism and ketosis, used as an alternative energy source for the brain and body.
• 1,3-Butanediol: A ketone precursor and alcohol compound that is metabolized into beta-hydroxybutyrate (BHB) in the liver.
• MCT Oil (Medium-Chain Triglyceride): A type of saturated fat that is readily absorbed and converted into ketones, commonly used in ketogenic diets.
• Creatine Monohydrate: A supplement that helps regenerate ATP in muscles, known for improving exercise performance, strength, and potentially cognitive function.
• Lipopolysaccharide (LPS): A component of gram-negative bacterial cell walls used in research to induce systemic inflammation and study immune responses.
• Ezetimibe (Zetia): A prescription medication that lowers cholesterol by inhibiting its absorption in the small intestine.
• Rapamycin: An immunosuppressive drug originally used to prevent organ rejection that has gained attention for potential anti-aging and longevity effects.
• Metformin: A first-line medication for type 2 diabetes that lowers blood glucose levels and has potential benefits for longevity and metabolic health.
• Berberine/Dihydroberberine: Plant-derived alkaloid compounds with glucose-lowering effects similar to metformin, used for metabolic health support.
• GLP-1 Agonists: A class of diabetes medications that mimic incretin hormones to regulate blood sugar and promote weight loss, including drugs like semaglutide and tirzepatide.
• SGLT-2 Inhibitors: A class of diabetes medications that lower blood sugar by preventing glucose reabsorption in the kidneys, causing excess glucose to be excreted in urine.
• NAD Supplements: Supplements like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) designed to boost cellular NAD+ levels for potential anti-aging benefits.
• Idebenone / CoQ10 / Ubiquinol: Antioxidant compounds that support mitochondrial energy production and cellular health, with CoQ10 being essential for ATP synthesis.
• GABA / Phenibut: Gamma-aminobutyric acid and related compounds that have calming, inhibitory effects on the central nervous system.
• Diphenhydramine (Benadryl): An over-the-counter antihistamine commonly used for allergies that causes drowsiness and is sometimes used as a sleep aid.
• Melatonin: A hormone naturally produced by the pineal gland that regulates the sleep-wake cycle and is commonly used as a sleep supplement.
• Ostarine: A selective androgen receptor modulator (SARM) that selectively targets muscle and bone tissue, mentioned for veterinary use in research contexts.
• Alpha GPC / Theanine: Nootropic compounds where Alpha-GPC supports acetylcholine production for cognitive function and L-theanine promotes relaxation without sedation.

Products & Brands

• KetoStart (Audacious Nutrition): A ketone electrolyte supplement company founded by Dr. Dominic D’Agostino’s wife, specializing in exogenous ketone products.
• Qitone: A brand that produces ketone diester powder supplements for enhancing ketosis and metabolic performance.
• Keto-Mojo: A company that manufactures portable blood glucose and ketone testing devices popular among those following ketogenic diets.
• Abbott Precision Xtra: A dual-purpose blood glucose and ketone monitoring system manufactured by Abbott for diabetes management and ketosis tracking.
• LMNT: An electrolyte supplement brand that provides sugar-free, keto-friendly hydration products with optimal sodium, potassium, and magnesium ratios.
• Levels: A metabolic health company that provides continuous glucose monitors (CGMs) paired with an app to help users optimize their blood sugar responses.
• Stelo: An over-the-counter continuous glucose monitor developed by Dexcom for people without diabetes to track their glucose patterns.
• GB HealthWatch: A genetic testing company that provides personalized reports for dyslipidemia and cardiovascular risk assessment based on DNA analysis.
• Dry Farm Wines: A wine company specializing in natural, low-sugar, additive-free wines that are lab-tested for purity and lower alcohol content.
• French Women Don’t Get Fat: The Secret of Eating for Pleasure by Mireille Guiliano: A bestselling lifestyle guide that reveals the “French paradox” of how French women stay slim while enjoying bread, wine, and three-course meals through principles of balance, quality over quantity, and eating for pleasure rather than restriction.
• Keto Brainz: A supplement brand that produces MCT powder enhanced with nootropic compounds to support both ketosis and cognitive function.
• Nutricost / Quest: Popular supplement brands that offer MCT powder products among their extensive product lines.
• Nordic Naturals: A premium omega-3 supplement brand known for high-quality fish oil products with third-party purity testing and sustainable sourcing.
• OmegaQuant: A testing company that measures omega-3 fatty acid levels in blood to help individuals optimize their omega-3 status and cardiovascular health.
• Metabolic Mind: An educational platform from the Baszucki Group that focuses on metabolic approaches to mental health and psychiatric conditions.
• MetPsy: An app currently in development designed to provide metabolic therapy coaching and support for mental health applications.

Institutions

• NIH (National Institutes of Health): The primary agency of the United States government responsible for biomedical and public health research.
• USF (University of South Florida): Public research university in Tampa where Dr. D’Agostino is a professor.
• Byrd Alzheimer’s Center: Research institute at USF Health dedicated to Alzheimer’s disease prevention, treatment and cure where Dr. D’Agostino’s wife worked.
• Buck Institute for Research on Aging: Independent biomedical research institute in California focused on extending healthy years of life.
• Harvard University: Private Ivy League research university in Cambridge, Massachusetts where Chris Palmer and Georgia Ede are affiliated.
• Moffitt Cancer Center: National Cancer Institute-designated comprehensive cancer center in Tampa collaborating with Dr. D’Agostino.
• Stanford University: Private research university in California where Shebani Sethi is affiliated.
• Oxford University: Prestigious collegiate research university in England where Dr. Ally Houston is affiliated.
• Northwestern University: Private research university in Illinois where Dr. Nav Chandel conducts research.
• University of Edinburgh: Public research university in Scotland where Dr. Iain Campbell conducts research.
• Yale University: Private Ivy League research university in Connecticut where Dr. Deep Dixit is a researcher.
• Genentech: American biotechnology corporation and subsidiary of Roche, pioneering in recombinant DNA technology.
• Metro International Biotech: Clinical-stage pharmaceutical company developing NAD+ precursors and therapeutics like MIB-626.

Relevant Resources & Research

• Meet Dr. Mary T. Newport — Neonatologist and Advocate for Treating Alzheimer’s with Ketones | Keto-Mojo
• Hyperbaric Oxygen Therapy Improves Post-Concussion Symptoms in Adults with Childhood Traumatic Brain Injury: A Retrospective Cohort Study | Frontiers in Neurology
• Enantiomer-Specific Cardiovascular Effects of the Ketone Body 3-Hydroxybutyrate | Journal of the American Heart Association
• The Many Faces of Beta-Hydroxybutyrate (BHB) | KetoNutrition
• Why Do We Need Both D-BHB and L-BHB? | KetoNutrition
• Study of the Ketogenic Agent AC-1202 in Mild to Moderate Alzheimer’s Disease | Nutrition & Metabolism
• A New Way to Produce Hyperketonemia: Use of Ketone Ester in a Case of Alzheimer’s Disease | Alzheimer’s & Dementia Journal
• The Ketone Metabolite Beta-Hydroxybutyrate Blocks NLRP3 Inflammasome-Mediated Inflammatory Disease | Nature Medicine
• Exogenous Ketone Supplements Reduce Anxiety-Related Behavior in Two Rodent Models | Scientific Reports
• Elevated Plus Maze Test Combined with Video Tracking to Investigate the Anxiolytic Effect of Exogenous Ketogenic Supplements | JoVE
• Toxicological Evaluation of the Ketogenic Ester Bis-Hexanoyl (R)-1,3-Butanediol: Subchronic Toxicity in Sprague-Dawley Rats | Toxicology
• A Dietary Ketone Ester Mitigates Histological Outcomes of Nafld and Markers of Fibrosis in High-Fat Diet Fed Mice | American Journal of Gastrointestinal and Liver Physiology
• Therapeutic Use of the Ketogenic Diet in Refractory Epilepsy: What We Know and What Still Needs to Be Learned | Nutrients
• Metabolic Therapy with Deanna Protocol Supplementation Delays Disease Progression and Extends Survival in Amyotrophic Lateral Sclerosis (ALS) Mouse Model | PLOS ONE

People

• Mary Newport: Physician and author who pioneered the use of MCT oil for Alzheimer’s disease, founding medical director of newborn intensive care units in Florida.
• Steve Newport: Husband of Dr. Mary Newport, subject of a case report on using a ketone monoester for Alzheimer’s disease who experienced significant improvements.
• Sam Corcos: Co-founder and CEO of Levels, a health technology startup that uses continuous glucose monitors to help people understand how food affects their metabolic health.
• Richard Veech: NIH researcher who developed the beta-hydroxybutyrate monoester and studied ketones for cognitive decline and neurological disorders.
• Peter Attia: Physician and longevity expert, known for the “Four Horsemen” concept, host of The Drive podcast and author of the #1 New York Times bestseller Outlive.
• George F. Cahill Jr.: Scientist known for his historic fasting studies and research on metabolic physiology at Harvard Medical School.
• Thomas Seyfried: Professor and cancer researcher at Boston College, colleague of Dr. D’Agostino who studies metabolic approaches to cancer treatment.
• Fred Hatfield (“Dr. Squat”): Powerlifter and mentor to Dr. D’Agostino who used a ketogenic diet for metastatic prostate cancer treatment.
• Valter Longo: Researcher known for the Fasting Mimicking Diet and director of the USC Longevity Institute studying aging and disease prevention.
• Mike Dancer: Man whose experience with epilepsy and the ketogenic diet influenced Dr. D’Agostino’s research direction.
• Sam Henderson: Researcher who published early research on AC-1202 (MCT oil) for Alzheimer’s disease treatment.
• Jong Rho: Researcher who highlighted the importance of acetoacetate and acetone in seizure control mechanisms.
• Spencer Nadolsky: Physician who suggested Dr. D’Agostino might be a hyperabsorber of cholesterol based on his lipid profiles.
• Matt Kaeberlein: Aging researcher and professor at the University of Washington studying longevity and healthspan extension.
• Csilla Ari D’Agostino: Neuroscientist, Dom’s wife, and founder of Audacious Nutrition.
• Charles Poliquin: Late strength coach known for his innovative training methods and work with elite athletes worldwide.
• Dale Bredesen: Physician and researcher focused on Alzheimer’s disease treatment and prevention through the ReCODE protocol.
• Navdeep Chandel: Researcher at Northwestern University studying cellular metabolism and its role in health and disease.
• Andrew Huberman: Neuroscientist and professor at Stanford University, host of the popular Huberman Lab podcast on health and performance.
• Rhonda Patrick: Scientist and host of FoundMyFitness, specializing in nutrition, aging, and disease prevention through lifestyle interventions.
• Eric Verdin: President and CEO of the Buck Institute for Research on Aging, studying metabolism and aging processes.
• Vishwa Deep Dixit: Researcher at Yale University who studied the NLRP3 inflammasome and its role in metabolic health.
• Chris Palmer: Harvard psychiatrist and author of Brain Energy, advocate for metabolic psychiatry approaches to mental health treatment.
• Matt Baszucki: Son of David Baszucki, whose experience with bipolar disorder was treated with a ketogenic diet approach.
• Jan and David Baszucki: Founders of Roblox, philanthropists funding metabolic psychiatry research through the Baszucki Brain Research Fund.
• Shebani Sethi: Psychiatrist at Stanford University researching metabolic approaches to mental health treatment.
• Ally Houston: Researcher at Oxford University studying metabolism and brain function.
• Georgia Ede: Harvard-trained psychiatrist and author of Change Your Diet, Change Your Mind, specializing in nutritional psychiatry.
• Iain Campbell: Researcher at the University of Edinburgh studying bipolar disorder and metabolic interventions.
• Deanna Tedone: Individual with ALS who stabilized her condition using the “Deanna Protocol” nutritional approach.
• Angela Poff and Victoria Field: Colleagues of Dr. D’Agostino who run the Metabolic Health Initiative at the University of South Florida.

SHOW NOTES

• [00:00:00] Start.
• [00:14:43] Why I’m interested in ketogenic strategies for neurodegenerative prevention.
• [00:16:18] Mary and Steve Newport’s ketone-linked temporary cognitive improvements.
• [00:18:18] A mechanisms overview for Alzheimer’s/dementia.
• [00:21:25] The immune system as longevity’s “fifth horseman” — and why metabolic control is key.
• [00:22:04] How to measure ketones and GKI.
• [00:23:00] Fasting vs. ketogenic diet.
• [00:24:18] There’s nothing fishy about sardine fasting.
• [00:28:32] My hiatal hernia discovery and increased cancer risk concerns.
• [00:30:04] HSCRP as a superior biomarker to LDL for cardiovascular risk.
• [00:31:57] Glucose tolerance testing revelations and CGM importance.
• [00:31:57] Upgrading the metabolic machinery through keto without getting bored.
• [00:42:07] What do do if you, like Dom and me, are among the 30% who suffer from cholesterol hyperabsorption.
• [00:43:42] Dom’s day-to-day diet regimen.
• [00:45:56] How Dom optimizes his aging dogs with ketones, SARMs, and supplements.
• [00:51:30] Supplementing for sleep disruption while fasting.
• [00:55:41] Why Dom doesn’t have misgivings about melatonin.
• [00:59:15] Shingles prevention through fasting protocols.
• [01:00:15] Immune system modulation: Innate vs. adaptive, vegan vs. ketogenic.
• [01:03:54] Dom at 50-something: Current meal timing and composition.
• [01:05:57] Blue zone observations: Greek and Sardinian longevity habits.
• [01:08:16] Ketogenic diet initiation tips: MCT, electrolytes, and fasted cardio.
• [01:15:18] Ketone metabolic therapy for cancer.
• [01:18:15] The metabolic psychiatry revolution.
• [01:22:10] The soothing effects of hyperbaric oxygen and ketosis on seizure sufferers.
• [01:28:27] Metformin vs. berberine.
• [01:31:43] The low-dose neuroprotective potential of GLP-1 drugs.
• [01:34:58] NAD research: MIB-626 and stabilized forms for mitochondrial health.
• [01:39:48] Idebenone, CoQ10, and the Deanna protocol for ALS.
• [01:42:05] Dom’s supplement short list: CoQ10, creatine, ketones, vitamin D, melatonin.
• [01:44:43] KetoNutrition.org, Metabolic Health Summit, Audacious Nutrition, veteran-focused research protocols, and other parting thoughts.

DR. DOMINIC D’AGOSTINO QUOTES FROM THE INTERVIEW

“I think the beauty of ketogenic [therapy] is that it’s pleiotropic, right? Which means it’s many mechanisms working in synergy.”

— Dr. Dominic D’Agostino

“I think the best way to measure to suggest you’re in autophagy is a glucose ketone index after a period of fasting.”

— Dr. Dominic D’Agostino

“About 30 percent of the population hyperabsorbs cholesterol.”

— Dr. Dominic D’Agostino

“HSCRP is a better indicator of cardiovascular disease than LDL cholesterol. We know that now. [No one would believe it] If someone said that 10 years ago.”

— Dr. Dominic D’Agostino

“I wouldn’t go above three. Probably 1.5 to 2 millimolar range. That seems to be a level of ketones that safely does not produce a metabolic acidosis.”

— Dr. Dominic D’Agostino

“When we published the NLRP3, I got requests from Genentech and various pharmaceutical companies to go there and give a talk on the mechanism so they could drugify. And I would throw up a big flow chart of all these mechanisms, and I think they would get frustrated. And it was like, ‘Well, tell us the mechanism so we can make a drug out of this.’”

— Dr. Dominic D’Agostino

“I went on a vacation where I forgot melatonin and I slept like a baby probably because I was up every morning. The sun is the ultimate circadian synchronizer. I got off of melatonin to check my endogenous melatonin, and there was no suppression.”

— Dr. Dominic D’Agostino

“So we went to these blue zones and they just, at night after their dinner, the males will do a shot of alcohol, usually wine, but sometimes ouzo and they’re all in their nineties and hundreds, they’re in the blue zone. So it’s a universal characteristic.”

— Dr. Dominic D’Agostino

Want to hear the last time Dom was on the show? Listen to our previous conversation in which we discussed disease prevention, longevity, cancer, ketogenic diet mastery, the detoxifying effects of ketosis on pre-cancerous cells, how to jumpstart daily ketogenic cycles, “cheat” meals, and much more.