Summary
Dr. Dominic D'Agostino is a tenured associate professor at USF and researcher at the Institute for Human and Machine Cognition. This updated conversation covers the latest on ketones for brain protection and cognition, his "sardine fasting" protocol, practical diet rules, and his evolved views on metformin and melatonin.
Key Points
- Updated research on ketones for neuroprotection and cognitive enhancement
- "Sardine fasting" - a unique fasting-mimicking approach using sardines
- Practical diet rules that work in the real world
- Metformin revisited - what the latest research shows about longevity benefits and risks
- Melatonin - updated perspective on dosing and when to use it
- How to protect the brain and boost cognition through metabolic interventions
- The role of exogenous ketones vs dietary ketosis
Key Moments
D'Agostino discovered ketogenic diet through a Meryl Streep movie and military research
D'Agostino found the ketogenic diet through multiple sources in the same week -- a Meryl Streep epilepsy film, a connection whose son's seizures were controlled by keto, and a newspaper story about MCT oil improving an Alzheimer's patient's cognitive tests. He pitched it to the military, who wanted a drug version instead.
"They didn't like the idea of using this high fat diet. So they're like, come up with a ketogenic diet and a drug."
Keto as a nootropic: 30-40% more brain blood flow and stable energy when fasted
Fasting on keto increases brain blood flow 30-40% because the GI system frees up blood and oxygen. D'Agostino considers it the best nootropic he's tried. The diet is hypopalatable but hypersatiating -- fat and protein satiate the brain so cravings don't manage you. Save carbs for evening to stabilize overnight glucose.
"If you could make a nootropic that had the same effect as being fasted, that would be a blockbuster."
MCTs produce ketones even on a high-carb diet: different ketone sources explained
Three ways to get into ketosis -- a ketogenic diet (suppresses insulin), MCTs (force ketogenesis even with carbs present), or exogenous ketone salts bound to electrolytes. 1 millimolar of ketones supplies about 10% of brain energy. Ketone salts also replace the sodium lost from keto's diuretic effect, preventing keto flu.
"One millimolar of ketones would equate to about a 10% increase in brain energy metabolism. That's pretty significant."
Keto restores glutamate-GABA balance: why it controls seizures through multiple mechanisms
Most seizures result from excess glutamate. Keto activates the enzyme that converts glutamate to GABA, restoring neurotransmitter balance. It also works through enhanced brain energy metabolism, adenosine signaling, and reduced inflammation. Anti-seizure drugs bluntly sedate the brain; keto restores balance through multiple synergistic mechanisms.
"The ketogenic diet works through many mechanisms in synergy. By enhancing brain energy metabolism, the GABA, adenosine, and inflammation."
Some epilepsy patients are 'super responders' who are permanently cured by keto
Some epilepsy patients are super responders -- they use the ketogenic diet temporarily and never have seizures again, effectively cured. D'Agostino cautions against hypercaloric keto for bulking, as it spiked his LDL. Keto shines with mild calorie restriction, augmenting the natural fasted state.
"The ketogenic diet can be used and then the patient can get off of it and never get seizures again. We call these patients super responders."
Stay metabolically flexible: low-carb base with 50-100g carbs to keep glucose pathways open
D'Agostino recommends keeping 50-100g of carbs daily to maintain pyruvate dehydrogenase activity and metabolic flexibility. This lets you burn fat at rest but still use glucose for high-intensity training. For longevity, incorporate some form of ketosis regularly -- through IF, low-carb, or periodic strict keto.
"Glucose can be a very powerful performance-enhancing substance. I think of carbohydrates almost as the alternative fuel."
