#825: 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
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Podcast Summary
In this in-depth episode, Tim Ferriss sits down with Dr. Dominic D'Agostino, a tenured associate professor at the University of South Florida and one of the world's leading experts on ketogenic diets and exogenous ketones. Dr. D'Agostino shares cutting-edge research on metabolic psychiatry, revealing how ketones function as powerful signaling molecules beyond just fuel—acting as HDAC inhibitors that activate genes for antioxidant defense and directly inhibiting inflammasomes linked to chronic diseases (01:11:00). He discusses the "sardine fasting" protocol developed with legendary powerlifter Dr. Fred Hatfield, who achieved remarkable cancer remission using one can of sardines daily for a week each month (25:01), and explains why maintaining a glucose ketone index of 1-4 creates the optimal metabolic zone for neuroprotection and longevity while avoiding the anxiety-inducing effects of excessive ketone levels (41:03).
Speakers
Dr. Dominic D'Agostino
Tenured associate professor in molecular pharmacology and physiology at the University of South Florida Morsani College of Medicine and visiting senior research scientist at the Institute for Human and Machine Cognition. Former NASA Extreme Environment Mission Operations crew member with research supported by the Office of Naval Research, Department of Defense, and National Institutes of Health. Widely recognized as the leading expert on ketosis, exogenous ketones, and metabolic-based therapies for neurological disorders and cancer.
Tim Ferriss (Host)
Best-selling author and host of The Tim Ferriss Show, which has garnered over 1 billion downloads and featured world-class performers from various disciplines. Known for deconstructing tactics and strategies from top achievers that listeners can apply to optimize their own performance and lives.
Key Takeaways
Stack Ketones with MCT Oil for Maximum Effect
Combine exogenous BHB ketones with MCT oil rather than taking them separately. MCT not only increases BHB levels higher than either supplement alone, but also sustains that elevation by slowing absorption. (02:33) This synergy creates a more stable and prolonged ketotic state—crucial for maintaining the 1.2-2 millimolar sweet spot where ketones provide anxiolytic benefits without triggering anxiety spikes.
Master the Sardine Fast for Cellular Cleanup
Deploy targeted "sardine fasting"—consuming one can of sardines daily for one week per month while maintaining a ketogenic framework. This protocol provides adequate nutrition while creating caloric restriction that activates autophagy and achieves the therapeutic glucose-ketone index of 1-2. Dr. Fred Hatfield used this approach to extend his survival with metastatic prostate cancer by years beyond his initial prognosis. (25:01)
Leverage Morning Fasted Cardio to Accelerate Ketosis
Jump-start ketogenic adaptation with fasted low-intensity cardio upon waking, combined with strategic supplementation of MCT oil and ketone electrolytes. This rapidly depletes liver glycogen and upregulates fat oxidation enzymes, bypassing the dreaded "keto flu" while accelerating your transition into metabolic flexibility. (69:27)
Optimize Ketone Timing for Peak Performance
Target the 1.2-2 millimolar ketone range for maximum cognitive and anxiolytic benefits—above 3 millimolars triggers anxiety and metabolic acidosis. Use continuous glucose monitoring alongside ketone measurements to track your glucose-ketone index (GKI), aiming for 1-4 range rather than the standard American diet's 25-50 range for enhanced metabolic flexibility and neuroprotection.
Cycle Ketogenic Protocols Strategically
Implement situational ketosis rather than chronic ketogenic dieting—deploy strict keto for 3-week cycles, transition to 16:8 intermittent fasting, then maintain a low-carb Mediterranean baseline with periodic sardine fasts. This approach maximizes therapeutic benefits while preventing metabolic adaptation and maintaining dietary sustainability for long-term adherence.
Statistics & Facts
- About 30% of the population hyperabsorb cholesterol (compared to the previously thought 1%), which can cause LDL and ApoB levels to skyrocket on a ketogenic diet - Dom discovered this through genetic testing with GB HealthWatch. (42:00)
- The optimal ketone range of 1.2-2 millimolars has anxiolytic (anxiety-reducing) effects, but ketones above 3 millimolars can cause metabolic acidosis by changing blood pH as the respiratory and renal compensation systems become overwhelmed. (86:54)
- A University of South Florida $28 million study on hyperbaric oxygen therapy for traumatic brain injury represents "the most elaborate hyperbaric oxygen therapy study that has ever been done," using six quarter-to-half million dollar hard shell chambers with innovative sham controls. (108:42)
