Summary
Dr. Dominic D'Agostino discusses the science of therapeutic ketosis with Dr. David Perlmutter, covering how ketogenic diets and exogenous ketones can improve metabolic health and potentially slow neurodegenerative diseases. They review research showing arrested Parkinson's progression, slowed Alzheimer's decline, and a 70% risk reduction in Alzheimer's among diabetic patients using ketone-based interventions versus insulin alone.
Key Points
- Ketone bodies (beta-hydroxybutyrate) serve as an alternative brain fuel that bypasses impaired glucose metabolism in neurodegeneration.
- A study showed 70% reduced Alzheimer's risk in diabetic patients using ketone-based interventions compared to insulin alone.
- Therapeutic ketosis requires sustained blood ketone levels of 1-3 mmol/L, achievable through diet or exogenous ketones.
- Exogenous ketone supplements can provide neuroprotective benefits without requiring full dietary ketosis.
- Ketogenic diets reduce systemic inflammation by lowering NLRP3 inflammasome activation, a key driver of neuroinflammation.
- Metabolic flexibility -- the ability to switch between glucose and ketone burning -- is a marker of overall metabolic health.
Key Moments
439 registered clinical trials for ketogenic diets on ClinicalTrials.gov
Dr. D'Agostino highlights the explosive growth in ketogenic diet research, noting 439 registered clinical trials on ClinicalTrials.gov for ketogenic diets plus over 100 more for ketone supplementation, up from just three or four applications a decade ago.
"there's 439 registered clinical trials on clinicaltrials.gov right now for ketogenic diets, and actually that dropped very slightly from last year, which was like 450 or something, mostly because there's about 100 or more clinical trials on ketone supplementation."
Beta-hydroxybutyrate suppresses the NLRP3 inflammasome and reduces neuroinflammation
Dr. D'Agostino describes how beta-hydroxybutyrate functions as a powerful signaling molecule that suppresses the NLRP3 inflammasome, increases the GABA-to-glutamate ratio in the brain, and has epigenetic effects through histone beta-hydroxybutyration — mechanisms relevant to Alzheimer's, Parkinson's, and other neurological conditions.
"We published a paper in 2015 and I helped formulate the diet and nature medicine that showed the beta hydroxybutyrate can function as an NLRP3 in flamizome suppression actually."
Allulose as a functional rare sugar that lowers blood glucose and stimulates GLP-1 secretion
Dr. D'Agostino describes allulose as a rare sugar found in nature that is essentially non-glycemic and non-insulinogenic at only 0.2-0.4 calories per gram, while also stimulating GLP-1 secretion by 300-500% in rodent models — making it a unique sweetener with functional metabolic benefits.
"allulose is really fascinating so it's a rare sugar it's found in nature things like fig and it's even in wheat I think you know in various fruits so it's a rare sugar that is an epimer of fructose"
MCT oil as the poor man's ketone ester — crosses the blood-brain barrier and boosts ketone levels
Dr. D'Agostino calls MCT oil the poor man's ketone ester, explaining that it can elevate blood ketone levels independent of diet, cross the blood-brain barrier unlike long-chain fatty acids, and dramatically augment the therapeutic effect of exogenous ketones when combined together.
"I love MCT oil and I think it's like the poor man's ketone ester"
Insulin sensitivity restoration through ketosis — most Americans over 50 are insulin resistant
Dr. D'Agostino emphasizes that most Americans are insulin-resistant especially after age 50, and that the ketogenic diet is one of the most effective ways to restore insulin sensitivity by reducing the chronic insulin challenge on the body.
"Well, broadly speaking, most Americans are insulin-resistant. And after, especially after 50 in the 60s and 70s, pre-diabetes or people have overt diabetes,"