Ketosis for mood, cognition, and brain protection: Dr. Dom D'Agostino

Executive overview

Ketosis does more than burn fat — it reshapes brain chemistry, immune function, and metabolic resilience. Elevated beta-hydroxybutyrate lowers glutamate, raises GABA, and enhances the adaptive immune response, with applications spanning metabolic psychiatry, neurodegeneration, and cancer adjunct therapy.

For most people, strict ketosis doesn't need to be permanent. A low-carb Mediterranean diet with periodic one-week ketogenic blocks — targeting a glucose-ketone index of 1–4 — captures most of the protective benefits while remaining sustainable long-term.

The core insight: metabolic health is brain health, and periodic ketosis is one of the most potent levers available.

Established benefits of ketosis

• Quiets the brain: lowers glutamate, raises GABA — the same pathway targeted by alcohol and benzodiazepines, but without the toxicity
• Stimulates the adaptive immune response; University of Pennsylvania is studying this for CAR-T and checkpoint inhibitor enhancement
• Targets glycolytic microbes and cancer cells: the Spirochete Borrelia (Lyme) is 100% glycolytic; ~80% of cancers are highly glycolytic
• Slows tumor growth and augments response to radiation, chemo, and immunotherapy — not a cure, but a meaningful adjunct
• Reduces insulin and inflammation (HSCRP); both are now considered more atherogenic than LDL alone
• Rapid improvement in blood pressure via diuretic and natriuretic effects

Metabolic psychiatry

• Remission of major depression, bipolar, schizophrenia, and anorexia nervosa reported in patients switched to ketogenic diets
• Mechanism: ketones shift neuropharmacology toward GABA-dominant, stabilised brain states
• Field is expanding rapidly; largely funded by the Baszucki group

Metabolic memory and carryover effects

• Extended ketosis upregulates mitochondrial number and ketolytic enzymes — effects persist after the diet ends
• Analogy: like VO2 max or strength, the adaptation snaps back quickly on reintroduction
• Walter Longo's fasting-mimicking diet data: five days of fasting produces measurable cardiometabolic changes lasting up to three months
• This is the scientific basis for periodic ketogenic "blocks" rather than continuous keto

Why blood ketone readings can be misleadingly low

• Ketone meters measure circulating ketones — a function of production minus utilisation
• Metabolically fit individuals clear ketones 2–5x faster via upregulated MCT transporters and ketolytic enzymes
• Caloric deficit accelerates tissue uptake further, leaving little to measure in blood
• Breath acetone (from spontaneous decarboxylation of acetoacetate) is a more reliable indicator during fasting states
• Continuous ketone monitors (e.g. Cybio) lose sensitivity after the first week; calibration is not yet available in-app

Protein, gluconeogenesis, and staying in ketosis

• Liquid protein (whey) raises blood amino acids rapidly and can suppress ketosis via insulin
• Fat, fiber, and salt tighten the pyloric sphincter, slowing gastric emptying and blunting the gluconeogenic spike
• MCT oil added to protein meals further buffers the response by stimulating endogenous ketone production
• A large, very fatty, salty meal can activate stretch receptors → sympathetic nervous system → gluconeogenesis independent of amino acid load; a 15–20 min walk post-meal counters this via GLUT4 activation

Optimal ketosis targets and practical protocols

• Therapeutic sweet spot: blood ketones 1–2 mmol/L; glucose-ketone index (GKI) of 1–4
• Very high ketones (3–5+ mmol/L) cause reductive stress and energy toxicity — higher is not better
• For Alzheimer's prevention and general metabolic health: low-carb Mediterranean diet plus one week per month of strict ketosis
• During the ketogenic week: cut calories ~50% the first two days to ramp ketones quickly, then cruise
• Target GKI of 1–4 for at least three days of the week; this level triggers measurable autophagy
• Benefits from one week of ketosis appear to last ~three weeks, supporting a monthly cycle

Alzheimer's prevention: key biomarkers to track

• Fasting insulin: target 2–6 µIU/mL
• hs-CRP: target below 0.6 mg/L
• HbA1c and fasting glucose
• Omega-3 index and omega-6:3 ratio
• Vitamin B12 (deficiency causes reversible brain atrophy that mimics Alzheimer's)
• Magnesium
• DEXA scan annually for body composition (visceral fat tightly linked to brain health)
• CGM to personalise dietary response before metabolic disease sets in

Exogenous ketones: what to look for and what to avoid

• Evaluate any ketone supplement on four criteria: palatability, tolerability, pharmacokinetics, and toxicity
• 1,3-butanediol — found in ketone monoesters (~51% by weight) and diesters (~35%) — is metabolised via alcohol dehydrogenase, depleting hepatic NAD and ATP
• Chronic use in animal studies: fatty liver, sinusoidal dilation, elevated TNF-alpha; transaminases may remain normal even with underlying pathology
• 1,3-butanediol causes narcotic effects, dependency, and withdrawal — problematic especially for older adults with reduced alcohol-detoxification capacity
• A rapid ketone spike from ester products can trigger an insulin surge that suppresses endogenous ketogenesis, creating a hypoglycaemic dip
• Preferred alternatives: free-acid BHB, glycerol-based triesters, ketone electrolyte salts (D+L racemic), or liposomal formulations
• L-beta-hydroxybutyrate metabolises ~4–5x slower than D-BHB and may improve cerebral blood flow and cardiac output
• Safe MCT ceiling for most people: ~20 mL twice daily with food; empty-stomach use causes GI distress

Protein veggie days as a body composition lever

• Dom's practice: 2 days/week of protein + vegetables with only 50–100 g fat (vs. 300–350 g on keto days)
• Effect: rapid body-fat mobilisation — body accustomed to exogenous fat begins pulling from stores
• Re-entry into ketosis is fast (same day or next day) vs. 2–3 days after a carbohydrate refeed
• Protein is roughly doubled on these days (~300 g), timed after heavy compound lifts for muscle protein synthesis