All Things Ketones, How to Boost Cognition, Sardine Fasting, Diet Rules, & More — Dr. Dom D’Agostino

Tim Ferriss, who is APOE3/4 and worried about a family history of Alzheimer's, presses Dr. Dom D'Agostino on what ketogenic diets, exogenous ketones, and fasting each uniquely deliver. They cover the metabolic roots of Alzheimer's (glucose hypometabolism, neuroinflammation, possible infectious triggers), how D'Agostino fasts 'situationally' using 'sardine fasting' rather than water-only fasts, and his personal low-carb Mediterranean diet, supplements, and biomarker targets. The conversation digs into ketone measurement devices, hypercholesterol absorption and APOB management, metformin/GLP-1/SGLT2 and berberine, melatonin's safety, and NAD research. D'Agostino details his lab's work on ketones augmenting the adaptive immune system and cancer immunotherapy, plus metabolic psychiatry funded by the Bazookis (Roblox), and a large hyperbaric oxygen study at USF. He frames ketogenic therapies as pleiotropic, working through many mechanisms in synergy rather than one drug-able target.

• Alzheimer's is increasingly understood as a brain energy metabolism problem ('type 3 diabetes'), with glucose hypometabolism, neuroinflammation, and possibly infectious agents (herpes, Epstein-Barr, HSV) as drivers.
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• D'Agostino's 'sardine fasting' (one can of sardines per day for a week, monthly) put cancer patient Dr. Fred Hatfield into rapid remission from metastatic prostate cancer despite a three-month prognosis; he died years later of something unrelated.
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• HSCRP (high-sensitivity C-reactive protein) is now a better predictor of cardiovascular disease than LDL cholesterol, and a key biomarker to keep low for Alzheimer's and cancer.
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• A ketogenic diet augments the adaptive immune system while a vegan diet enhances the innate immune system (published in Nature Medicine); D'Agostino's lab uses ketone metabolic therapy to boost cancer immunotherapy.
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• Beta-hydroxybutyrate suppresses the NLRP3 inflammasome; a diet formulated to elevate BHB reproduced fasting's anti-inflammatory effect (Nature Medicine, 2015).
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• Metabolic psychiatry is being funded largely by Jan and David Bazooki (Roblox) after Chris Palmer treated their son Matt into durable remission; they match donations dollar-for-dollar for a major Oxford study.
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• D'Agostino's lab showed exogenous ketones produce an anxiolytic effect in animals comparable to a benzodiazepine, by raising the GABA-to-glutamate ratio in the brain.
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• USF is running a $28 million hyperbaric oxygen study for traumatic brain injury using a true sham control (pulsed pressure to fake pressurization), the most elaborate HBOT study ever done.
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• D'Agostino recommends the Keto Mojo meter for consumers because it auto-calculates the glucose ketone index (GKI); meters read about 10-20% high on glucose versus lab assays.
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• A glucose ketone index of 1 to 2 sustained for 3 to 5 days correlates with maximizing autophagy; normal US GKI is around 25 to 50.
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• About 30% of the population are cholesterol hyperabsorbers (not 1%); D'Agostino has an NPC1L1 gain-of-function mutation and takes half a 5mg ezetimibe tablet, which halves his LDL and APOB.
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• 50mg of diphenhydramine can impair memory recall acutely, but 25mg shows no such effect; D'Agostino limits it to about once a month and warns nightly use by the elderly may drive dementia.
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• D'Agostino takes 5mg melatonin as a neuroprotective agent (not for sleep); he tested 20-30mg doses and confirmed no endocrine/testosterone suppression in himself, unlike in hibernating animals.
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• Taking MCT with caffeine/coffee boosts ketone production by 20-30% (work by Stephen Cunnane), a 'ketogenic synergy.'
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• D'Agostino is in his 50s, weighs 218-220 lbs at 9.4% body fat, eats three meals a day of mostly fish, meat, eggs, and broccoli, and drinks low-sugar dry-farm wine most evenings.
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• He gives his male dogs exogenous ketones, the SARM ostarine (after injuries), creatine, and mushroom supplements; his 12-year-old Great Dane still runs 35 mph.
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• Ketogenic therapies are 'pleiotropic' (many mechanisms in synergy), which frustrated pharma companies wanting a single drug-able mechanism after the NLRP3 work.
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• D'Agostino's short list of supplements: creatine monohydrate (up to 20g/day split-dosed for Alzheimer's), exogenous ketones, vitamin D (target 60-80), melatonin, and CoQ10.
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