Summary
Peter Attia and neuroscientist Dom D'Agostino take a deep dive into metabolic therapies, covering practical approaches to nutritional ketosis with adequate protein, the landscape of exogenous ketones (salts vs. esters), and pairing strategies like caffeine and MCT. They also discuss ketogenic diets as therapy for glioblastoma and Alzheimer's, hyperbaric oxygen protocols and ongoing clinical trials, and when fasting and ketones work best as situational cognitive tools.
Key Points
- Nutritional ketosis with adequate protein (1.5g/kg+) is more sustainable and muscle-sparing than the classic high-fat, very-low-protein keto approach.
- Ketone esters outperform ketone salts for raising blood BHB but can be paired with caffeine and MCT for a more practical daily protocol.
- Hyperbaric oxygen therapy is being studied in clinical trials as a metabolic therapy for glioblastoma and Alzheimer's, with promising early results.
- Fasting and exogenous ketones work best as situational cognitive tools (e.g., before demanding mental work) rather than chronic interventions.
- The ketogenic diet as cancer therapy targets cancer cells' metabolic inflexibility -- they rely on glucose and cannot efficiently use ketones.
- Dom D'Agostino uses keto cycling: strict keto during focused research periods and more relaxed eating during social or travel periods.
Key Moments
How nutritional ketosis works — from fasting to fat oxidation
Dom D'Agostino explains the pathway from insulin suppression to ketone production, describing how beta-hydroxybutyrate and acetoacetate preserve brain energy metabolism during carbohydrate restriction.
"Ketosis, I like to start with fasting. So when you stop eating, you suppress the hormone insulin, you mobilize fatty acids for fuel. The brain's not a good, it can't use the long chain fatty acids that are stored in your adipose tissue. So through beta oxidation, if fatty acids in the liver, accelerated beta oxidation in the context of insulin suppression generates these molecules, beta hydroxybutyrate and acetyl acetate."
High protein keto for weight loss — the practical approach
For weight loss, D'Agostino recommends a high-protein, moderate-fat ketogenic diet with carbohydrates limited to high-fiber sources like broccoli and avocado.
"Yeah, weight loss. So I would say calories are super important. So just gravitate towards a high protein ketogenic diet. And if it's just purely weight loss, I would say high protein, moderate fat, and then high fiber. So the carbohydrates that you're getting should be just fibers carbohydrates. So you can get 50 to even 100 grams of carbs per day if one third of those carbohydrates are fiber."
Higher protein keto boosts GLP-1 and weans the brain off glucose
A higher-protein ketogenic diet increases GLP-1, reverses insulin resistance, and fundamentally transitions the brain away from glucose dependence, with ketone electrolytes smoothing the transition.
"So with a higher protein diet, you're getting higher GLP1, you're reversing insulin resistance, you're improving fatty acid oxidation. And I think you're fundamentally weaning your brain off glucose. Your brain has, is dependent on glucose with a standard American. And as you're decreasing glucose availability, your brain has a counter regulatory dysphoric reaction to that."
Exogenous ketones lower glucose independent of carb restriction
D'Agostino notes that exogenous ketone supplementation lowers blood glucose even without dietary carbohydrate restriction, likely through enhanced insulin sensitivity rather than just insulin secretion.
"With that said, exogenous ketone supplementation tends to lower blood glucose independent of carbohydrate restriction."
Protein was underappreciated in early ketogenic diets
Modern ketogenic practice has shifted toward higher protein than the original 90% fat diet, as even pediatric epilepsy clinics now favor modified versions with 60-70% fat.
"are about 60 to 70% fat. With higher protein, now we know, especially in kids, you restrict protein too much, you could stunt their growth and have some issues there. So clinically, a modified version of the ketogenic diet is actually being gravitated more towards even in pediatric epilepsy. So we're learning that protein is really important. And it was underappreciated, I guess,"
