#825: Dr. Dominic D’Agostino — All Things Ketones, How to Protect the Brain and Boost Cognition, Sardine Fasting, Diet Rules, Revisiting Metformin and Melatonin, and More

Hello, boys and girls, ladies and germs. Tim Ferriss here. Today I am going deep with Dr. Dominic D’Agostino on all things ketones, brain protection, performance, and some wild but practical protocols. Quick hits from my notes: pairing exogenous beta-hydroxybutyrate with MCT raises and sustains ketones more than either alone; ketones are powerful signaling molecules, not just fuel—think anti-inflammatory and epigenetic effects; watch chronic one, three-butanediol esters for potential liver issues; aim for a glucose ketone index of roughly one to four and a ketone sweet spot around one point two to two millimolar for calm focus; higher spikes can trigger anxiety and a crash. We also get into sardine fasting, melatonin myths, and using ketones with hyperbaric oxygen. Buckle up.

I have relatives with neurodegeneration, and I am ApoE three four myself. What is the best evidence and most promising direction for ketogenic diets or exogenous ketones to prevent or slow Alzheimer’s—practically and mechanistically?

I saw the power of ketones firsthand with Steve Newport—ApoE three four with Alzheimer’s and Lewy body dementia—who became animated and steady for hours after coconut and MCT oil shots, then declined as ketones fell, and reanimated when ketones returned to roughly one to two millimolar. Mechanistically, aging brains show glucose hypometabolism—decreased GLUT3 transport, reduced pyruvate dehydrogenase activity, neuroinflammation, and likely infectious triggers in a subset—so ketones bypass the glucose bottleneck and dampen inflammation. For measuring, I still publish with Abbott Precision Xtra but recommend Keto-Mojo for day-to-day; it auto-calculates GKI and aligns well with our biological assays.

Help me contrast fasting versus ketogenic diet versus exogenous ketones. I used to do one-week fasts annually and three-day fasts quarterly. What do you personally do now, and what actually moves the needle?

I fast situationally and lean on a sardine fast for most benefits without the downsides of water-only. Dr. Fred Hatfield had metastatic prostate cancer and did low carb plus roughly one week per month of one can of sardines per day—he went into rapid remission and lived many years with no evidence of disease. For me and for cancer patients, sardine fasting supplies omega-3s and micronutrients, avoids cachexia, suppresses insulin and mTOR, likely nudges AMPK, and reliably drives a GKI of about one to two for three to five days—a strong proxy for autophagy activation.

Quick gear check: my Keto-Mojo glucose ran higher than phlebotomy during an OGTT. Should I worry—and should people pair that with CGM and insulin testing?

Fingerstick meters tend to read high—Keto-Mojo about ten percent and Precision Xtra closer to twenty percent above our lab assays—so do not panic. A CGM plus fasting insulin and an oral glucose tolerance test will catch issues missed by fasting glucose snapshots; that is why I advise CGM and platforms like Levels for real-world patterns.

On exogenous ketones: if I cycle strict keto, then 16 to 8 fasting, then more paleo and add ketones during my fasted window—how do I keep benefits for cognition and Alzheimer’s risk as ApoE three four without burning out on strict keto?

I would run a low-carb Mediterranean baseline you can do every day, then drop into deeper ketosis situationally to keep GKI roughly one to four. Track insulin, hsCRP, hemoglobin A1C, triglycerides, ApoB, and Lp(a). Approximately thirty percent of people hyperabsorb cholesterol; I am one of them and respond dramatically to ezetimibe—half a tablet cut my ApoB in half—so genetics matter. Carbs around fifty to one hundred grams with roughly twenty five percent of those carbs as fiber works well for me: fibrous vegetables and wild berries, minimal starch and sugar. Swapping heavy cream, moderating egg yolks, and favoring fish like small mackerel and sardines helped my LDL while keeping keto benefits.

Do you use rapamycin? And would you ever use it for your dogs?

I am not using rapamycin; too many mouth sores and immune concerns in people I know. Bigger levers for me: periodic ketosis and sardine fasting. For our two older, neutered male dogs, I use a selective androgen receptor modulator to preserve muscle and bone, plus fish, meat, eggs, ketones, creatine, a mushroom blend, and lots of daily activity on the farm.

Fasting wrecks my sleep—racing heart, electrolyte dump. What do you use to make sardine fasting or early keto easier at night?

I take ketone electrolytes with beta-hydroxybutyrate two to three times per day, plus MCT, and eat the sardines at night. For sleep: magnesium, GABA, five to ten milligrams of melatonin, and occasionally twenty five milligrams of diphenhydramine to reduce sleep latency—but not habitually, given the dementia data with chronic anticholinergics. Phenibut can work at very low, infrequent doses but is risky. I have used melatonin nightly for years; human data do not show endocrine suppression, and my own labs show no LH or FSH suppression—even after large stress-tests—so I use it more as a neuroprotective than as a sedative.

Would you ever do water-only fasting now—or is sardine fasting your default? And what is this shingles story I keep hearing?

I still use water-only fasting situationally; for example, early shingles tingling often aborts if someone starts fasting immediately. Fasting and ketosis shift immunity—lowering inflammatory cytokines while enhancing adaptive responses—and beta-hydroxybutyrate suppresses the NLRP3 inflammasome. Caveat: be cautious if malnourished or on chemo; context matters.

What does your daily diet look like now, including alcohol?

I eat three meals: eggs with chub mackerel for breakfast; fish or meat at lunch; and a big dinner—often a pound of beef, chicken, or fish—with lots of broccoli. We eat earlier now and I train or do farm work afterward. I enjoy one glass of lower-alcohol wine with activity; I see better sleep and labs, and wine decreases platelet aggregation. I aim for roughly thirty grams of fiber daily from vegetables, berries, and a small apple.

Fastest way to get into keto without the keto flu? And best way to use MCT—especially when traveling or at altitude?

Start with fasted, low-intensity cardio, hydrate, and use electrolytes. Add small, frequent doses of MCT and ketone salts to raise ketones while your own ketogenesis ramps; avoid big ester doses early. In rodents we see transporter upregulation by approximately two weeks; humans likely need weeks to months for full adaptation. I use MCT powder in coffee in the morning—caffeine plus MCT has a nice ketogenic synergy—and I avoid caffeine after noon, using MCT powder in hot water later if needed. Alpha-GPC can give me headaches, so I keep it low.

What current projects have you most excited—cancer, Alzheimer’s, metabolic psychiatry? For what it is worth, my labs, OGTT, and mood have all improved cycling keto with esters.

On cancer, we published a framework for ketone metabolic therapy in glioblastoma and are testing whether beta-hydroxybutyrate enhances checkpoint inhibitors and CAR-T by expanding key T-cell populations. On metabolic psychiatry, I would point folks to Chris Palmer; in our lab, acute ketosis with ketone salts plus MCT produced benzodiazepine-like anxiolysis in animals and shifted brain neurochemistry toward higher GABA to glutamate. Clinically I aim for one to two millimolar ketones; above roughly three can become anxiogenic and acidifying. Metformin can nudge ketones and improve markers in dysmetabolism but has risks like lactic acidosis and photosensitivity; berberine is a gentler cousin; GLP-1s are a different, powerful tool largely via calorie reduction and brain-gut effects.

I am primarily interested in low-dose GLP-1 for potential neuroprotective effects. Also, do you use berberine, or is it unnecessary if diet keeps glucose in check?

Low-dose is prudent; higher doses are not well studied long-term. I tried dihydroberberine—it lowered my post-meal glucose but gave me headaches within a week, possibly via vascular effects or altered caffeine metabolism—so I stopped. For people not cutting carbs, GLP-1 and SGLT2 inhibitors can be effective, physician-guided levers. I also front-load caffeine early and avoid it later to protect sleep.

For elderly patients who cannot reliably follow a diet, meds and weekly injections seem practical. Do you take anything specifically for mitochondrial health?

Ketones shine for mitochondria—both D and L beta-hydroxybutyrate. We are studying NAD therapeutics with Metro International Biotech, including stabilized forms like MIB six-two-six; oral NR and NMN are largely taken up by the liver and muscle and may not reach the brain. NAD fuels hundreds of enzymes and sirtuins, and DNA repair depends on it. Redox balance matters—too much NADH relative to NAD can be problematic—so we are refining ketone formulations, dose, timing, and personalizing therapy with continuous ketone and glucose monitoring and, potentially, lactate.

Do you still take idebenone, the more absorbable CoQ10?

CoQ10 is on my short list, especially if you are on statins or metformin, though I get plenty from organ meats and do not supplement. Idebenone is a drug form I discussed in the context of the Deanna Protocol for ALS; it became a standard for certain ataxias and is harder to source, so ubiquinol or CoQ10 can substitute. Caution: in rodents, very high doses of potent CoQ10 forms caused kidney issues; that may not reflect typical consumer products.

What else is on your short list?

Creatine monohydrate is a staple; exogenous ketones are emerging. For advanced Alzheimer’s, I would consider ten to twenty grams of creatine per day split into multiple five-gram doses if tolerated. Vitamin D, but dose to your labs—I keep it around sixty to eighty, not over one hundred. Melatonin at night for neuroprotection. I do not take omega-three because my DHA and EPA are high from sardines, but testing with OmegaQuant is useful; if you do not eat fish, Nordic Naturals has worked for me. I expect omega-three status will become standard blood work.

I use creatine the same way—twenty grams today after poor sleep—and splitting doses helps.

Anything else you want to point people to?

At our Alzheimer’s center we are developing approximately twenty alcohol-free ketogenic compounds and running preclinical Alzheimer’s studies. I am also excited about a twenty-eight million dollar mild hyperbaric oxygen study at the University of South Florida with a rigorous sham design; forty to sixty sessions may improve cognition and reaction time even years after traumatic brain injury in veterans. Oxygen is a powerful drug, and this should give a clear answer for TBI with or without post-traumatic stress. I would pair ketone therapy to enhance benefits and lower oxygen-toxicity seizure risk. The facility can also aid oncology; hyperbaric oxygen is covered for radiation necrosis and may enhance selected treatments.

We will link everything in the show notes at tim dot blog slash podcast—search Dominic. Thanks for the time; I took a lot of notes and will have more questions. Until next time, be a bit kinder than is necessary. It matters—to others and to yourself. And as always, thanks for tuning in.