#845: How to Use Ketosis for Enhanced Mood, Cognition, and Long-Term Brain Protection — A Practical and Tactical Guide with Dr. Dominic D'Agostino (Plus: Deconstructing Tim’s Latest Keto Experiment)

Tim Ferriss introduces a practical discussion on ketosis with Dom D'Agostino, covering benefits, implementation, challenges, and exogenous ketones. Tim shares his month-long experiment using continuous glucose and ketone monitors, seeking Dom's advice for fine-tuning his approach. Benefits include reduced sleep needs, mental sharpness, stabilized mood, and potential neuroprotection. Dom D'Agostino's background is highlighted, emphasizing his expertise in metabolic therapies for neurological disorders and human performance optimization. The conversation promises a wide-ranging and practical exploration of ketosis.

Dom D'Agostino and Tim Ferriss begin their discussion by establishing the benefits of ketosis, which Dom says mirrors the benefits of fasting but without the metabolic drawbacks. Ketosis quiets the mind, which has implications for mental health. Ketosis elevates GABA and lowers glutamate, which can silence seizures. Dom notes the broad application of ketosis for metabolic psychiatry, including major depression, bipolar disorder, schizophrenia, anxiety disorders, and anorexia nervosa, largely funded by the Bazooki Group.

Beyond cognitive and psychiatric benefits, ketosis is effective for weight loss due to fluid and sodium loss, which lowers blood pressure. It helps lower insulin levels and shifts metabolism to burning fats, stimulating ketone production. Tim shares his experience using a cyclical ketogenic diet in the 90s for mood stabilization and muscle building. He also recounts how ketosis helped him recover from cognitive symptoms and joint pain associated with Lyme disease, leading him to recommend it to friends with similar tick-borne disease symptoms.

Tim Ferriss details his experience using ketosis to combat Lyme disease symptoms, noting the disappearance of cognitive and joint pain. Dom D'Agostino explains that the spirochete Borrelia, which causes Lyme disease, is glycolytic, meaning it relies on glucose for energy. Limiting glucose availability through ketosis targets the microbe's energy systems. Ketosis, specifically elevated beta-hydroxybutyrate, stimulates the adaptive immune response, enhancing the body's ability to neutralize foreign invaders. This augmentation of the immune response helps keep the spirochete in a dormant stage or potentially eradicate it.

Tim Ferriss explains his use of ketosis for mood stabilization and its potential protective effects against neurodegenerative diseases like Alzheimer's. He notes the stabilizing effect on mood without muting the highs. He also finds it easier to enter ketosis now that he practices intermittent fasting. Dom D'Agostino confirms the existence of metabolic memory, similar to muscle memory, where the body adapts to ketosis, making it easier to enter and derive benefits over time.

Dom D'Agostino emphasizes that muscle memory is metabolic memory, highlighting the body's ability to quickly re-establish VO2 max after time off. Tim Ferriss details his current routine, combining intermittent fasting with a ketogenic diet. He consumes two meals a day, including a mackerel-based meal with MCT oil and apple cider vinegar, which he finds surprisingly delicious and cost-effective. He notes the easy transition into ketosis due to his prior intermittent fasting practice.

Tim Ferriss describes his use of a Dexcom continuous glucose monitor and a CyBio continuous ketone monitor to track his ketosis. He expresses confusion over consistently low ketone readings, despite feeling sharp and experiencing the benefits of ketosis. His glucose levels are also lower than expected. He questions how he can function with such low readings, seeking Dom D'Agostino's interpretation of these results.

Tim Ferriss questions the impact of protein intake on gluconeogenesis and ketosis. Dom D'Agostino explains that rapid entry of amino acids into the bloodstream, such as from whey protein, can shut off ketosis. He recommends consuming protein with fat, fiber, and salt to slow gastric absorption and buffer the gluconeogenic response. MCT oil can further augment this effect.

Tim Ferriss asks about the impact of a large bunless double cheeseburger on ketosis. Dom D'Agostino says that a big meal can activate the sympathetic nervous system, enhancing gluconeogenesis. The mechanoreceptors in the stomach signal to the brain, triggering hormonal responses that can affect glucose production.

Tim Ferriss asks about the optimal timing for walks after meals to mitigate glucose spikes. Dom D'Agostino recommends walking immediately after a meal to activate glucose transporters, reduce insulin release, and use sympathetic nervous system mobilization of glucose, which attenuates the buffering of ketogenesis.

Tim Ferriss notes that continuous glucose and ketone monitors are not designed for someone like him, making it difficult to interpret the data. He relies on subjective feel, but seeks advice on how to better read the tea leaves. He also shares his surprise at maintaining or even enhancing muscle mass while intermittent fasting and following a ketogenic diet.

Tim Ferriss asks about rabbit starvation and whether one can rely on body fat for fuel while consuming lean protein on a ketogenic diet. Dom D'Agostino shares his experience of incorporating protein and veggie days into his ketogenic diet, noting that it helped him lose body fat. He emphasizes that keto trains fat metabolism, and titrating in protein and veggies can pull fat out.

Tim Ferriss asks if a ketogenic diet can benefit or delay the onset of neurodegenerative diseases like Alzheimer's. Dom D'Agostino says that improving cardio-immunometabolic biomarkers is key. Lowering insulin and inflammation, optimizing omega-3 to 6 ratio, and addressing B12 deficiencies are important. Ketone metabolic therapy impacts factors driving age-related chronic diseases, including Alzheimer's.

Tim Ferriss shares a personal story of a relative with rapidly advancing Alzheimer's, highlighting the importance of addressing metabolic dysfunction and the potential cognitive damage from estrogen blockers. He seeks advice on the minimum effective dose of a ketogenic diet for neuroprotection, given his aversion to long-term adherence.

Dom D'Agostino suggests that Tim Ferriss can get 80% of the benefits with a low-carb diet and periodic ketosis, enhancing metabolic flexibility. He emphasizes the importance of diverse food intake to prevent micronutrient deficiencies. He also highlights the value of CGMs for personalized dietary insights and the role of exercise, particularly resistance training, in neuroprotection.

Tim Ferriss asks about the optimal frequency of ketosis: one week per month versus three contiguous weeks per quarter. Dom D'Agostino suggests that either pattern can be beneficial, but the one-week intervention could be more aggressive. He recommends aiming for a glucose ketone index (GKI) of 1 to 2 for at least three days out of that week.

Tim Ferriss and Dom D'Agostino discuss the glucose ketone index (GKI) and how to calculate it. Tim expresses concern that his low ketone readouts, likely due to improved insulin sensitivity, make it difficult to determine if he's hitting his target GKI.

Dom D'Agostino suggests expanding the GKI range to 1 to 4, as the published literature supports its therapeutic benefits. He emphasizes that even a millimolar concentration of one in the blood has energetic and vascular benefits, increasing blood flow to the brain.

Tim Ferriss and Dom D'Agostino discuss exogenous ketones, covering palatability, tolerability, pharmacokinetics, and toxicity. Dom emphasizes the importance of considering these factors when selecting a ketone supplement, particularly for long-term use.

Dom D'Agostino warns about the toxicity of 1,3-butanediol, a common ingredient in ketone esters. Chronic use can deplete the liver of NAD and ATP, leading to inflammation, sinusoidal dilation, and fatty liver. He notes that 1,3-butanediol is metabolized through alcohol dehydrogenase and aldehyde dehydrogenase, producing a toxic byproduct.

Dom D'Agostino discusses the translation of animal model findings to humans, noting that 1,3-butanediol can elevate transaminases (liver enzymes) in humans. He emphasizes that normal transaminases do not always indicate a healthy liver, as non-alcoholic fatty liver disease can exist with normal enzyme levels.

Dom D'Agostino notes that the field is trending towards non-1,3-butanediol-based exogenous ketones, such as free acids, triesters, and ketone salts. He believes that formulation is key to optimizing ketone supplements and averting potential problems.

Tim Ferriss asks how MCT oil helps with ketone monoester consumption. Dom D'Agostino explains that MCT oil delays gastric absorption and stimulates endogenous ketone production. However, large doses of MCT oil can lead to fatty liver and inflammation. He also notes that ketone monoester can cause insulin spikes, potentially hindering endogenous ketone production.

Tim Ferriss questions whether he should have a ketogenic breakfast instead of intermittent fasting. Dom D'Agostino suggests that protein in the morning can rev up metabolism, but Tim prefers the mental sharpness of fasting. Dom also warns about the potential for 1,3-butanediol to create dependence and withdrawal symptoms.

Dom D'Agostino explains that 1,3-butanediol has narcotic-like properties and can cause alcohol-like withdrawal symptoms. Tim Ferriss recounts his experience of feeling "smashed" after consuming a small amount of 1,3-butanediol. Dom warns that 1,3-butanediol can be dangerous for older people due to its narcotic effects and reduced liver detoxification capacity.

Tim Ferriss asks about Dom D'Agostino's favorite sources of fiber on a ketogenic diet. Dom recommends broccoli, wild blueberries, and apples. He notes that wild blueberries have less sugar and more fiber than regular blueberries.

Tim Ferriss asks about the carbohydrate limits for apples and berries on a ketogenic diet. Dom D'Agostino shares that he consumes about 60 to 70 grams of carbs per day from these sources, but one-third of the carbs is fiber. He also notes that adding carbs back into his diet has helped him maintain his body weight and enjoy beneficial fiber and phytonutrients.

Dom D'Agostino shares a cautionary tale about consuming gummies that were likely contaminated with a potent substance, causing severe dizziness and incapacitation. He emphasizes the importance of product safety and being cautious about supplements.