Joe Rogan Experience #2575 - Sam Tallent

Episode Overview

• Dr. Dominic D'Agostino tells Dr. Rhonda Patrick how nutritional ketosis, caloric restriction, and exogenous ketones affect brain bioenergetics, metabolic health, longevity, athletic performance, and cancer therapy.
• The conversation begins by defining clinical ketosis and explaining how ketones bypass insulin resistance to fuel the aging or diseased brain, offering therapeutic potential for epilepsy, Alzheimer's disease, and psychiatric disorders.
• Next, they examine the metabolic and cardiovascular impacts of ketogenic diets, discussing type 2 diabetes reversal, why LDL cholesterol spikes in certain individuals, and how animal longevity studies link caloric restriction and time-restricted feeding to daily ketosis.
• Finally, they cover practical implementation strategies, including preserving muscle mass, measuring ketones, using exogenous ketone supplements (MCTs, salts, and esters), and pairing ketogenic metabolic therapy with standard cancer treatments.

Key Concepts

• Clinical Nutritional Ketosis and Brain Bioenergetics: Clinical nutritional ketosis starts at a blood beta-hydroxybutyrate (BHB) level of 0.5 millimolar (mM) and goes up to 3 to 5 mM, whereas levels above 5 mM are typically only seen in prolonged fasting or starvation ketosis. A blood ketone level of 1.0 mM provides roughly 10% of the brain's energy, and Harvard studies by George Cahill and Owen using radio-labeled tracers showed that after 7 to 10 days of fasting or low-carbohydrate dieting, ketones (BHB and acetoacetate) supply 60% to 70% of brain energy. Classic experiments by Richard Veech and George Cahill demonstrated the resilience of ketone metabolism: when subjects in therapeutic ketosis (4 to 5 mM) were injected with insulin to crash their blood glucose to 1.0 mM (and 0.5 mM in one subject, a level that normally causes immediate coma and death), they remained completely asymptomatic because ketones sustained their brain energy.
• Insulin-Independent Brain Transport and Neurodegeneration: Ketones cross the blood-brain barrier via monocarboxylic acid transporters (MCT1 and MCT2), operating completely independently of insulin and glucose transporters (GLUT1, GLUT3, and GLUT4). This matters for aging and neurodegeneration because, as Dr. Stephen Cunnane demonstrated using dual-tracer PET scans (FDG-PET for glucose and acetoacetate-PET for ketones) in patients with mild cognitive impairment (MCI) and Alzheimer's disease, brain glucose metabolism declines with pathology while brain ketone metabolism remains completely intact and increases when blood ketones rise. Over a dozen phase 1, phase 2, and phase 3 clinical trials now show positive cognitive effects from ketogenic interventions in Alzheimer's and dementia.
• Diet Formulations vs. Caloric Deficit: A classic clinical ketogenic diet for pediatric epilepsy consists of 85% to 90% fat (a 4:1 or 3:1 ratio of fat to combined protein and carbohydrates) alongside a 10% to 15% (and sometimes 20% in institutional settings) caloric restriction. By contrast, the Modified Atkins Diet (MAD) pioneered by Eric Kossoff at Johns Hopkins uses 65% to 75% fat, higher protein, and more liberalized low-glycemic carbohydrates. However, ketosis is ultimately driven by insulin suppression and glycogen depletion rather than fat intake alone: a person could consume 1,000 calories of pure white table sugar per day and still enter mild ketosis if they maintain a 1,000-calorie daily deficit. Similarly, Jeff Volek's FASTER study showed that elite endurance athletes eating 3,000 to 4,000 calories with 100 to 150 grams of carbohydrates daily stayed in nutritional ketosis because their high exercise output continually depleted glycogen stores.
• Neuroinflammation and Psychiatric Applications: Beyond serving as a metabolic fuel, BHB is a signaling molecule. Research by Dr. Melanie Stefan (formerly of D'Agostino's lab, now at Edinboro Medical School) shows that BHB protects against anxiety and depression by inhibiting the NLRP3 inflammasome, which reduces neuroinflammation. Clinically, Harvard psychiatrist Dr. Chris Palmer uses the ketogenic diet to treat schizophrenia, bipolar disorder, and severe treatment-resistant depression, helping patients reduce or eliminate antipsychotic medications and avoid antipsychotic-induced ponderal syndrome (severe weight gain and type 2 diabetes).
• Type 2 Diabetes Reversal and the LDL-C Caveat: In 2-year published data (with 3- to 5-year ongoing data) from Virta Health, coaching type 2 diabetes patients on a ketogenic diet resulted in a 50% to 60% reversal of the disease, allowing roughly two-thirds of patients to eliminate insulin and most to stop taking sulfonylureas and metformin. Across 22 or 26 cardiovascular biomarkers tracked in the 2-year study, every biomarker improved except for LDL-C (and sometimes ApoB), which crept up slightly though stayed within normal ranges for most diabetic subjects. In lean, athletic individuals (the "Lean Mass Hyper-Responder" phenotype), strict ketogenic diets can drive LDL-C to 300 to 500 mg/dL. D'Agostino stresses that "the jury is still out" on whether an isolated rise in LDL-C and ApoB causes atherosclerosis when triglycerides, hs-CRP, and insulin are low and HDL is high, pointing to Dave Feldman and Dr. Matthew Budoff's ongoing CT angiogram study at UCLA to answer this question.
• Longevity, Caloric Restriction, and Post-Translational Modifications: D'Agostino's lab has tested ketogenic diets and ketone supplements across 6 different animal models, extending survival and lifespan in all 6, while independent Cell Metabolism studies by Eric Verdin (Buck Institute) and Jon Ramsey (UC Davis) showed that feeding a ketogenic diet to middle-aged mice improved both healthspan and lifespan. D'Agostino argues that classic caloric restriction (restricting food by 20% to 30% in lab rodents) extends lifespan primarily because the animals gorge their daily food ration within 2 to 4 hours and fast for the remaining 20 to 22 hours; Comprehensive Lab Animal Monitoring System (CLAMS) data proves their Respiratory Exchange Ratio (RER) drops to 0.7, indicating pure fat oxidation and daily ketosis. Fasting and ketosis also induce the "succinylome" and "acetylome," which are post-translational modifications where succinyl-CoA and acetyl-CoA accumulate and bind to lysine residues on proteins, altering gene expression and enzyme activity independently of DNA methylation or histone acetylation. However, D'Agostino cautions that while ketogenic diets clearly improve human healthspan, we do not know if they will extend maximal human lifespan to 120 or 130.
• Time-Restricted Feeding and Fasting Mimicking Protocols: Compressing the eating window yields longevity and metabolic benefits even without reducing calories. Rafael de Cabo's work at the NIH showed that isocaloric time-restricted feeding in mice extended longevity and improved liver histology compared to continuous ad libitum feeding, even on high-sugar diets. Satchin Panda's lab similarly demonstrated that restricting mice on a high-fat, high-sugar diet to an 8- to 12-hour feeding window protected them from obesity, fatty liver, and premature death compared to ad libitum mice eating the exact same calories. Additionally, Dr. Valter Longo's 4- to 5-day low-calorie, low-protein Fasting Mimicking Diet (FMD) lowers IGF-1 and temporarily shrinks organ size, stimulating stem cell proliferation and visceral fat loss upon refeeding while sparing lean mass.
• Anti-Catabolic Effects of Ketones and the Protein Longevity Paradox: Rather than being directly anabolic like insulin or IGF-1, ketones are profoundly anti-catabolic. Elevating blood BHB significantly reduces circulating alanine, an amino acid released from skeletal muscle breakdown for gluconeogenesis. While rodent longevity studies suggest restricting protein and methionine to lower IGF-1, both Patrick and D'Agostino emphasize that mouse cages do not reflect human aging, where sarcopenia and frailty are major threats. Research by Hiroshi Bando in Japan on elderly populations, as well as D'Agostino's collaborations with Dr. Jacob Wilson and Jeff Volek on resistance-trained athletes, shows that consuming 1.6 to 2.0 grams of protein per kilogram of body weight (25% to 30% of calories) on a ketogenic diet preserves kidney function, prevents sarcopenia, and allows athletes to gain muscle while losing fat.
• Ketone Testing and the Glucose Ketone Index (GKI): Blood BHB meters (such as Precision Xtra or Keto-Mojo) represent the gold standard for tracking ketosis, whereas breath meters (Biosense, Readout Health) measure acetone in parts per million (ppm) and urine strips (Ketostix) measure acetoacetate. Urine strips often become misleading over time because keto-adaptation causes the kidneys to upregulate monocarboxylate transporters, reabsorbing filtered acetoacetate back into the blood rather than excreting it. For therapeutic applications, D'Agostino's lab—which receives funding from the Office of Naval Research (ONR) and the Department of Defense (DoD) to study central nervous system oxygen toxicity in warfighters—relies on the Glucose Ketone Index (GKI), a metric originally developed by Dr. Thomas Seyfried at Boston College for glioblastoma. In preclinical rodent models of oxygen toxicity, reaching a blood BHB of 2.0 mM or a GKI under 2.0 (e.g., glucose at 4.0 mM and ketones at 2.0 to 4.0 mM) delayed central nervous system seizures by 500% to 600%.
• Exogenous Ketones and D-BHB vs. L-BHB Pharmacokinetics: Exogenous ketones come in several forms (

Quotes

• At 0:05:17 - "Nutritional ketosis is really defined clinically by reaching a blood ketone level of beta-hydroxybutyrate of 0.5 millimolar and up to say 3 to 5 millimolar." - Dr. Dominic D'Agostino establishing the clinical biomarker boundaries for nutritional ketosis before transitioning into starvation ketosis above 5 mM.
• At 0:06:16 - "George Cahill showed that after about 7 to 10 days of fasting, upwards of 60 to 70 percent of brain energy is derived from ketones, beta-hydroxybutyrate and acetoacetate." - Dr. Dominic D'Agostino explaining how the human brain shifts its primary fuel source away from glucose during prolonged carbohydrate restriction or fasting.
• At 0:13:51 - "You could eat 1,000 calories of table sugar a day and if you are creating a 1,000 calorie deficit, you are going to be in a state of mild ketosis because the calorie restriction will suppress the hormone insulin enough so you liberate fatty acids and oxidize them." - Dr. Dominic D'Agostino illustrating the counterintuitive reality that total energy deficit and insulin suppression can trigger ketogenesis regardless of dietary macronutrient composition.
• At 0:20:32 - "They infused insulin into fasting subjects to drop their blood glucose down to 1 millimolar, and in one subject 0.5 millimolar, which would normally cause coma and death, and the subjects were completely asymptomatic because their ketones were at 4 to 5 millimolar." - Dr. Dominic D'Agostino recounting the classic Cahill and Veech experiments that proved ketones can fully sustain brain bioenergetics during severe hypoglycemia.
• At 0:21:44 - "Stephen Cunnane has shown using dual-tracer PET scans—FDG-PET for glucose and acetoacetate-PET for ketones—that in patients with mild cognitive impairment and Alzheimer's disease, glucose metabolism goes down, but ketone metabolism in the brain remains completely intact." - Dr. Dominic D'Agostino explaining the physiological rationale for using ketogenic interventions to bypass cerebral glucose hypometabolism in Alzheimer's disease.
• At 0:28:18 - "Beta-hydroxybutyrate is not just a metabolic fuel, it's a signaling molecule that inhibits the NLRP3 inflammasome, which reduces neuroinflammation that is now recognized as a primary driver of treatment-resistant depression and anxiety." - Dr. Dominic D'Agostino detailing the anti-inflammatory mechanism behind the psychiatric benefits of ketosis researched by Dr. Melanie Stefan.
• At 0:34:39 - "Virta Health has published 2-year data showing a 50 to 60 percent reversal of type 2 diabetes using a nutritional ketosis intervention, with about two-thirds of patients completely eliminating their need for exogenous insulin." - Dr. Dominic D'Agostino highlighting clinical trial outcomes for reversing metabolic disease through medically supervised ketogenic diets.
• At 0:39:05 - "I don't even like to call it a high-fat diet anymore; if you look at my plate, it is one-third fish or meat and two-thirds vegetables like broccoli or asparagus, and then I add fat in the form of extra virgin olive oil or MCTs." - Dr. Dominic D'Agostino describing how he structures a well-formulated, Mediterranean-style ketogenic diet around whole foods and monounsaturated fats.
• At 0:44:27 - "When I was consuming 2 to 3 containers of 4% cottage cheese and heavy cream every day, my hs-CRP crept up and my LDL went over 200; when I eliminated the excess dairy fat and switched to olive oil and fish, those markers completely normalized." - Dr. Dominic D'Agostino sharing his personal experience with dairy saturated fats driving up inflammation and LDL cholesterol.
• At 0:45:43 - "In our medical student study, individuals who had LDL cholesterol go up into the 300 to 500 range on a strict ketogenic diet saw their LDL drop by 200 to 300 points within just a few weeks simply by adding back 50 to 100 grams of carbohydrates." - Dr. Dominic D'Agostino citing Andrew Koutnik's Frontiers in Nutrition study on resolving the Lean Mass Hyper-Responder LDL spike with modest carbohydrate reintroduction.
• At 0:53:46 - "My perspective is that calorie restriction extends lifespan in rodent models primarily because it puts the animals into a daily state of mild to moderate nutritional ketosis." - Dr. Dominic D'Agostino connecting classic longevity research on caloric restriction directly to ketone metabolism.
• At 0:55:24 - "When you calorie restrict a mouse in a lab by 20 or 30 percent, they gorge and eat all of their food in 2 to 4 hours, which means they are fasting for 20 to 22 hours a day and their respiratory exchange ratio drops right down to 0.7." - Dr. Dominic D'Agostino explaining how laboratory feeding schedules inadvertently turn caloric restriction studies into intermittent fasting and ketosis studies.
• At 1:02:02 - "Satchin Panda's work really hammered this home: mice eating the exact same high-fat, high-sugar diet, same exact calories, just compressed into an 8 to 12 hour window, are completely protected from obesity, fatty liver, and premature death." - Dr. Rhonda Patrick emphasizing the metabolic power of time-restricted feeding independent of caloric intake or diet quality.
• At 1:07:37 - "If you keep protein intake at 1.6 to 2.0 grams per kilogram of body weight on a ketogenic diet and incorporate resistance training, you do not lose lean body mass—in fact, our studies with Jacob Wilson showed athletes can gain muscle while losing fat." - Dr. Dominic D'Agostino refuting the misconception that ketogenic diets cause muscle wasting when adequate protein is consumed.
• At 1:12:41 - "Ketones are profoundly anti-catabolic rather than anabolic; when you elevate blood beta-hydroxybutyrate, you see a dramatic decrease in circulating alanine, meaning the body stops breaking down skeletal muscle for gluconeogenesis." - Dr. Dominic D'Agostino explaining how elevated ketones spare muscle tissue during energy deficits.
• At 1:15:39 - "Urine ketone strips measure acetoacetate, and as you become keto-adapted over weeks, your kidneys upregulate monocarboxylate transporters to reabsorb those ketones, so your urine strips might read negative even when your blood BHB is 2.0 millimolar." - Dr. Dominic D'Agostino explaining why long-term keto dieters should rely on blood meters rather than urine strips.
• At 1:19:48 - "In our Department of Defense oxygen toxicity seizure models, getting blood ketones above 2.0 millimolar and a Glucose Ketone Index under 2.0 delayed central nervous system seizures by up to 500 to 600 percent." - Dr. Dominic D'Agostino sharing preclinical data from his DoD-funded warfighter resilience research.
• At 1:26:59 - "Medium chain triglycerides like C8 caprylic acid and C10 capric acid do not require the carnitine shuttle to enter the mitochondria; they go straight through the portal vein to the liver and are obligately converted into ketone bodies." - Dr. Dominic D'Agostino detailing the biochemical pathway that allows MCT oil to generate ketones rapidly.
• At 1:41:44 - "While D-beta-hydroxybutyrate is rapidly oxidized for ATP, the L-isomer—L-beta-hydroxybutyrate—lingers in the bloodstream and brain much longer, where it still acts as a potent signaling molecule to inhibit the NLRP3 inflammasome and suppress ROS." - Dr. Dominic D'Agostino revealing mass spectrometry insights into why racemic ketone salts containing L-BHB offer prolonged anti-inflammatory benefits.
• At 1:51:20 - "Lou Cantley showed in Nature that PI3K inhibitors fail in cancer patients because the drug causes an insulin spike that reactivates the tumor; when he put the animals on a ketogenic diet to block that insulin spike, the drug worked across almost every tumor type tested." - Dr. Dominic D'Agostino illustrating how a ketogenic diet can rescue failing pharmaceutical cancer therapies when used as an adjuvant.

Takeaways

• Adopt a Mediterranean-Style Ketogenic Plate: Instead of eating heavy amounts of bacon and butter, visually structure your plate as one-third fish, chicken, or beef and two-thirds fibrous, low-carbohydrate vegetables (such as broccoli, asparagus, and salad greens), adding healthy fats primarily through extra virgin olive oil, fatty fish, and MCTs.
• Adjust Dairy and Carbohydrates if LDL or CRP Spikes: If following a strict ketogenic diet drives up your inflammatory markers (hs-CRP) or pushes your LDL-C above 200 to 500 mg/dL, eliminate excess dairy fats (like heavy cream, sour cream, and cottage cheese) in favor of olive oil and fish, and consider adding back 50 to 100 grams of whole-food carbohydrates (such as berries, rice, or oatmeal) daily, which has been shown to drop LDL-C by 200 to 300 points within 2 to 4 weeks.
• Eat 1.6 to 2.0 g/kg of Protein to Preserve Muscle: To prevent age-related sarcopenia and build or maintain lean mass on a ketogenic diet, pair resistance training with 1.6 to 2.0 grams of protein per kilogram of body weight (roughly 25% to 30% of total calories) rather than restricting protein to classic epileptic diet levels.
• Compress Your Feeding Window to 8 to 12 Hours: Leverage the longevity and liver-protective benefits of intermittent ketosis by practicing time-restricted eating (such as an 8- to 12-hour feeding window or a 16:8 fasting protocol), which lowers insulin and promotes daily fat oxidation even when total calories remain constant.
• Prevent the "Keto Flu" with Electrolytes: When transitioning into ketosis or fasting, actively supplement with sodium, potassium, and magnesium to counteract the natriuresis of fasting (the kidney's excretion of sodium and water caused by low insulin), preventing plasma volume depletion, orthostatic hypotension, headaches, and fatigue.
• Track Ketosis with Blood BHB Meters Instead of Urine Strips: Use a clinical blood ketone meter (like Precision Xtra or Keto-Mojo) or a breath acetone meter (like Biosense) rather than urine Ketostix, as kidney upregulation of monocarboxylate transporters during keto-adaptation causes acetoacetate reabsorption and false-negative urine readings.
• Target a Glucose Ketone Index (GKI) of 1.0 to 2.0 for Therapeutic Needs: If utilizing ketosis for severe neurological protection or managing disease states, measure both blood glucose and blood ketones (in mM) to keep your GKI between 1.0 and 2.0 and your blood BHB at 2.0 mM or higher.
• Titrate MCT Oil Slowly and Emulsify It: To elevate ketones via C8 caprylic and C10 capric acid without suffering gastrointestinal distress ("disaster pants"), start with just 1 teaspoon (5 ml) of MCT oil and slowly build up to a maximum of 1 to 2 tablespoons (15 to 30 ml) per dose, ideally emulsifying the oil into coffee or a protein shake.
• Combine Balanced Ketone Salts with MCT Oil for Sustained Elevation: For a 3- to 4-hour sustained rise in blood BHB with minimal gastric hypermotility, pair MCT oil in a 1:1 or 2:1 ratio with a racemic ketone electrolyte salt (which provides both ATP-generating D-BHB and slow-clearing, anti-inflammatory L-BHB) formulated with a balanced blend of four minerals (sodium, potassium, calcium, and magnesium) to avoid sodium overload.
• Avoid Chronic High-Dose Ketone Esters on a High-Carb Diet: Reserve potent ketone esters (which spike blood BHB to 3.0 to 5.0 mM in 30 minutes) for acute cognitive or athletic performance needs rather than taking massive doses multiple times daily alongside a high-carbohydrate diet, avoiding the unstudied "metabolic conflict" of simultaneously high insulin, glucose, and ketones.
• Use Periodic Fasting Mimicking Protocols for Cellular Regeneration: For individuals who do not want to follow a year-round ketogenic diet, consider incorporating a 4- to 5-day low-calorie, low-protein Fasting Mimicking Diet (FMD) periodically to temporarily lower IGF-1, reduce visceral fat, and trigger stem cell proliferation upon refeeding.
• Apply Ketogenic Diets as an Adjuvant—Never a Replacement—in Cancer Care: If navigating cancer, work with an oncologist to use a calorie-restricted ketogenic diet as an adjuvant metabolic therapy to suppress tumor-feeding insulin spikes and sensitize cancer cells to standard treatments (such as PI3K inhibitors, chemotherapy, radiation, or hyperbaric oxygen therapy), never as a standalone replacement for standard medical care.