#845: How to Use Ketosis for Enhanced Mood, Cognition, and Long-Term Brain Protection — A Practical and Tactical Guide with Dr. Dominic D'Agostino (Plus: Deconstructing Tim’s Latest Keto Experiment)
Timestamps are as accurate as they can be but may be slightly off. We encourage you to listen to the full context.
Podcast Summary
In this comprehensive discussion, Tim Ferriss joins Dr. Dominic D'Agostino midway through an 18-day ketosis experiment to explore the practical implementation of ketogenic dieting. (00:13) Tim shares his experience wearing both continuous glucose and ketone monitors while following a strict ketogenic protocol, revealing unexpected challenges with low ketone readings despite feeling mentally sharp and energized. The conversation delves deep into the mechanisms behind ketosis benefits, from mood stabilization and cognitive enhancement to potential neuroprotective effects. (05:26) They discuss Tim's remarkable recovery from Lyme disease-related cognitive symptoms through ketosis, with Dom explaining the scientific basis for why ketogenic interventions work against tick-borne illnesses and other inflammatory conditions.
- Core Theme: Practical ketogenic diet implementation, troubleshooting common challenges, and understanding the science behind ketosis benefits for cognitive enhancement, mood stabilization, and potential disease prevention.
Speakers
Tim Ferriss
Tim Ferriss is a bestselling author, entrepreneur, and host of The Tim Ferriss Show podcast. He's known for his systematic approach to self-experimentation and optimization, having written multiple books including The 4-Hour Body and Tools of Titans.
Dr. Dominic D'Agostino
Dr. Dominic D'Agostino 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. His research focuses on nutritional strategies and metabolic-based therapies for neurological disorders, psychiatric conditions, cancer, and human performance optimization, with funding from the Office of Naval Research, Department of Defense, and NIH.
Key Takeaways
Intermittent Fasting Creates Metabolic Memory for Easier Ketosis Transitions
Tim discovered that six months of intermittent fasting (eating between 2PM-9PM) dramatically improved his transition into ketosis. (28:46) Unlike previous attempts where he experienced "keto flu" symptoms, this transition was seamless with no brain fog or low energy. Dom explains this occurs because intermittent fasting depletes liver glycogen and triggers metabolic switching around the 16-hour mark, essentially training your body for fat oxidation. This creates what Dom calls "metabolic memory" - similar to muscle memory, where your metabolic machinery becomes more efficient at switching between fuel sources. For professionals seeking cognitive benefits from ketosis, establishing a consistent intermittent fasting routine first can eliminate the challenging adaptation period and make periodic ketogenic interventions much more manageable.
Low Ketone Readings May Indicate Superior Metabolic Health, Not Failure
Tim was frustrated by consistently low ketone readings (0.1-0.4 millimolar) despite feeling mentally sharp and energized. (36:00) Dom revealed this likely indicates enhanced insulin sensitivity and superior ketone utilization rather than failure at ketosis. When metabolically fit, your body becomes highly efficient at using ketones, meaning blood measurements reflect what's left over after tissues have consumed what they need. Dom compares this to a motorcycle engine running lean - when you're using fuel efficiently, there's less "spillover." This explains why elite athletes and metabolically healthy individuals often show lower blood ketone readings despite being in deep ketosis. The key insight: subjective feelings of mental clarity and energy are more reliable indicators than blood measurements for healthy individuals.
Strategic Meal Timing and Composition Prevents Gluconeogenesis Disruption
Dom emphasizes that protein timing and meal composition critically affect ketosis maintenance. (41:39) Consuming large amounts of protein rapidly (like whey shakes) can shut off ketosis by flooding the bloodstream with amino acids. However, combining protein with fat, fiber, and salt slows gastric emptying through the pyloric sphincter, creating a steady amino acid release that doesn't trigger significant gluconeogenesis. Tim's approach of having smaller protein-rich meals with adequate fat (like canned mackerel with MCT oil) followed by larger mixed meals demonstrates this principle perfectly. For busy professionals, this means you can maintain ketosis while getting adequate protein by being strategic about meal composition rather than obsessing over exact gram counts.
The Glucose-Ketone Index (GKI) Provides Therapeutic Precision
Dom recommends targeting a Glucose-Ketone Index (GKI) of 1-4 for therapeutic benefits, calculated by dividing glucose (in millimolar) by ketones. (84:51) For example, glucose of 80 mg/dL (4.4 millimolar) with ketones at 1.0 millimolar equals a GKI of 4.4. During therapeutic interventions, Dom suggests achieving a GKI of 1-2 for at least three days to maximize benefits like autophagy activation and metabolic adaptation. This provides a more precise target than simply aiming for ketosis, allowing individuals to optimize their interventions. For prevention-focused individuals, maintaining this range during weekly or monthly ketogenic periods could provide significant long-term benefits while allowing dietary flexibility the rest of the time.
Exogenous Ketones Require Careful Selection to Avoid Toxicity
Dom warns that many popular exogenous ketone supplements contain 1,3-butanediol, which can cause liver toxicity with chronic use. (99:59) This compound is metabolized like alcohol and can cause dependency, withdrawal symptoms, and elevated liver enzymes (AST, ALT, GGT). Dom's research shows that even healthy individuals can experience liver enzyme elevation after two weeks of moderate dosing. He recommends capping 1,3-butanediol intake at 20 milliliters daily and not using it continuously. Safer alternatives include ketone salts (like BHB salts) or formulations that combine multiple compounds to minimize individual component risks. For professionals considering exogenous ketones for cognitive enhancement, choosing products without 1,3-butanediol and using them strategically rather than daily provides benefits while avoiding potential health risks.
Statistics & Facts
- Tim reported needing only 6-6.5 hours of sleep while in ketosis compared to his usual 8-9 hours, with improved alertness upon waking. (01:44) This sleep efficiency improvement is one of the most immediate and noticeable benefits of achieving therapeutic ketosis levels.
- Dom explains that 80% of cancers are highly glycolytic, meaning they depend heavily on glucose for energy. (20:20) This makes ketogenic interventions particularly valuable as an adjunct to standard cancer treatments by limiting the primary fuel source these cancers depend on.
- Research shows that 1 millimolar concentration of beta-hydroxybutyrate in blood represents approximately 10% of available energy for the brain. (89:02) This demonstrates how even seemingly low ketone levels can provide significant cognitive benefits and alternative brain fuel.
