#116 - AMA with Dom D'Agostino, Ph.D., Part I of II: Ketogenic diet, exogenous ketones, and exercise

Episode Summary

Executive Summary: This AMA sneak peek centers on Dom D'Agostino’s work on ketosis, ketogenic diets, and ketone measurement, with emphasis on intermittent ketosis, practical books and devices, and how ketones relate to exercise, fasting, and metabolic flexibility. Dom also previews ongoing research on NASA analog missions, cancer cachexia, and genetic diseases, while noting that the discussion is informational and not medical advice.

Main Topics: Intermittent ketosis and metabolic flexibility (Priority: 5/5): Dom argues that even healthy people may benefit from periodic ketosis because it can improve metabolic flexibility, create a kind of metabolic memory, and deliver fasting-like benefits without prolonged fasting. Ketone measurement tools and interpretation (Priority: 5/5): The discussion compares urine strips, blood meters, and breath acetone devices, with Dom favoring blood beta-hydroxybutyrate for routine use and breath acetone as a promising, increasingly quantitative alternative. Ketones, exercise, and substrate utilization (Priority: 4/5): Dom explains how exercise can lower ketone readings by increasing utilization, and suggests breath acetone may reflect ketone/fat oxidation and clearance, especially in athletes and during fasting. Books and educational resources on keto (Priority: 3/5): Dom recommends several books spanning layperson, performance, clinical, and scientific perspectives, including key texts by Phinney/Bollock, The Ketogenic Bible, Keto Answers, and Oxford’s ketogenic therapies volume. Current research directions (Priority: 4/5): Dom outlines ongoing work on NASA extreme-environment missions, cancer cachexia, Kabuki syndrome, and other metabolic therapies, highlighting efforts to translate lab science into human applications. Ketones, insulin, and fasting physiology (Priority: 4/5): The conversation revisits classic fasting physiology and emphasizes insulin suppression as a major driver of ketogenesis and fat mobilization, with implications for exogenous ketones and metabolic signaling.

Key Arguments: Intermittent ketosis can be useful even for healthy people because it may improve metabolic flexibility and provide benefits similar to fasting. A restricted ketogenic diet combined with time-restricted feeding can mimic many fasting effects, including insulin suppression and likely autophagy-related signaling. Blood beta-hydroxybutyrate remains the most practical and validated routine ketone measure, but breath acetone is a strong proxy for fat oxidation and may be especially useful clinically. Breath acetone readings can be distorted by alcohol or recent meals, so timing and conditions matter for accurate interpretation. Exercise tends to lower ketone levels because ketones are being used as fuel; a rebound rise after exercise reflects increased fat oxidation and ketogenesis. Exogenous ketones may have therapeutic value, but their effects on endogenous ketone production and insulin need careful mechanistic interpretation. Dom’s research is increasingly focused on translating ketosis into human studies, including space analogs and disease models. The ketogenic field now has a strong educational ecosystem, with books ranging from practical guides to deep scientific references.

Data Points: Time since prior podcast appearance: Almost 2 years - Bob notes Dom’s last appearance with Peter was nearly two years earlier, in summer 2018. NASA mission number: Mission 22 - Dom says he was a crew member for NASA extreme environment mission operations research mission 22. NASA mission number: NEMO 23 - Dom’s wife was a crew member for NEMO 23. Restricted ketogenic duration suggested: 5 to 7 days - Dom suggests doing five to seven days of restricted ketogenic eating monthly to approximate fasting benefits. Alternative monthly protocol: 6 days - He also mentions six days of restricted ketogenic diet per month as a practical fasting alternative. Calorie restriction level: 50% - Dom proposes a 50% calorie-restricted ketogenic diet as one way to target fasting-like effects. Target glucose ketone index: 1 to 2 - Dom says this range is a useful target for intermittent ketosis and fasting-like benefit. Ketone ratio: 4 to 1 - He states a typical beta-hydroxybutyrate to acetoacetate ratio is about four to one. Alternative ketone ratio observed: 6 to 1 - Dom notes some measurements show beta-hydroxybutyrate to acetoacetate ratios as high as six to one. Breath meter calibration: 1 to 2 minutes - He says the Biosense breath acetone device takes about a minute or two to calibrate. Breath acetone scale: 10 ACEs ≈ 1.0 beta-hydroxybutyrate - Dom says 10 ACEs on the breath meter roughly correlates with 1.0 mmol/L beta-hydroxybutyrate. Insulin infusion example: 20 IUs - He references a graph showing effects after an IV infusion of 20 IUs of insulin.

Pivotal Quotes: "I think there's definitely benefits that you can derive out of, I guess what you'd call intermittent ketosis." — Dom D'Agostino: Explaining why healthy people might still use periodic ketosis. "I believe when you go into a state of ketosis, whether you do it with ketogenic diet or fasting, it changes, it actually activates a genetic program that actually can allow you to burn fat and make ketones more efficiently." — Dom D'Agostino: Describing metabolic adaptation and memory from repeated ketosis. "Breath acetone is a very strong indicator of fat oxidation." — Dom D'Agostino: Discussing why breath testing may be useful beyond blood ketone measurement.

Implications: Listeners can view ketosis as a flexible tool rather than an all-or-nothing diet. The episode points toward more personalized keto use, better monitoring tech, and expanding clinical research in exercise, space medicine, and disease treatment.