Dr. Dominic D’Agostino on Developing a Well-​​Designed Ketogenic Diet and Harnessing Its Benefits

Ketogenic Diets and Ketosis

• Ketogenic diet: unique dietary therapy defined by an objective biomarker (ketones)
  • Measure ketones in blood, urine, and breath
  • Must be in a state of hyperketonemia (elevated ketones) to be on a ketogenic diet
• Classical ketogenic diet (4:1) used for pediatric epilepsy 
  • 90% fat, with a level of carbohydrates that has almost no effect on insulin
  • Mimics fasting: low insulin, low IGF‑1, suppression of mTOR
• Modified Atkins or low glycemic index therapy (LGIT) — a more liberal version of the ketogenic diet 
  • Produces a mild state of ketosis
  • Can still have therapeutic effects, even with low ketones
• Variations of the ketogenic diet used clinically 
  • 5:1, 4:1, 3:1, 2:1, modified Atkins, LGIT
  • All have therapeutic effects for different neurological disorders, seizure disorders, and metabolic disorders
  • Efficacy depends on the individual and compliance

Starting a Ketogenic Diet

• Context-​​dependent
  • For managing metabolic or brain disorders, start with a clinical ketogenic diet under supervision
  • For lifestyle approach, transition into a ketogenic diet over 4–6 weeks 
    • Titrate carbohydrates down gradually
    • Improves adherence and reduces side effects
• Abruptly starting a ketogenic diet can cause side effects and lipid abnormalities

Mild State of Ketosis

• Achieved through a more liberal version of the ketogenic diet
• Can still have therapeutic effects, even with low ketones
• Benefits from low ketones include improved mood, reduced anxiety, and better sleep
  Modified Ketogenic Diet and Fiber
• Transition to a ketogenic diet is easier with calorie restriction 
• Modified ketogenic diet: 10–20% carbohydrates in the form of fibrous vegetables 
  • Leafy greens, non-​​glycemic carbohydrates
  • Fiber helps slow digestion, improve protein assimilation, and maintain gut microbiome
• Fiber is important for gut health and fueling colonocytes
• Cooking vegetables can make carbohydrates more accessible, impacting glycemic response
• Example of a modified ketogenic diet meal: fatty fish, leafy greens, extra virgin olive oil, MCT oil, nuts

Ketogenic Diet and Insulin Response

• Order and combination of food can impact glycemic response
• Incorporating fat and fiber with a meal can help attenuate insulin response
• Protein intake (e.g., whey protein) can kick one out of ketosis due to insulin response

Ketogenic Diet Contraindications and Biomarkers

• Ketogenic diet is widely accepted for epilepsy and metabolic disorders
• Contraindicated for inborn errors of metabolism (e.g., carnitine transferase deficiency)
• APOE4 allele carriers (25% of the population) may not respond well to extremely high-​​fat diets 
  • Moderate approach with carbohydrate restriction and fiber intake recommended
• Monitoring biomarkers (e.g., glucose response, hypoglycemia) is important when transitioning to a ketogenic diet
  Ketogenic Diet and Ketone Supplements
• Importance of fiber, micronutrients, and phytonutrients in diet 
• Selenium deficiency and cardiomyopathy linked to ketogenic diet
• APOE4 gene and diet 
  • Moderate fat, protein, and plant-​​based fiber
  • Focus on monounsaturated fats, MCT oils, omega‑3 fatty acids
  • Avoid high saturated fat for APOE4 carriers
• Ketone supplements
  • Ketone salts, ketone esters, MCT oils/​​powders
  • Can mimic many effects of ketogenic diet without strict dietary adherence
  • Beneficial for cognition, health span, and various conditions
  • Numerous clinical trials currently underway
  • Ketones as the “next creatine” in terms of research and potential benefits

Ketone Supplements and Neurological Effects

• Ketones as alternative energy sources and signaling molecules 
  • Elevate adenosine, activate ketone receptors, reduce inflammation, and decrease oxidative stress
• Exogenous ketones can replicate many neurological benefits of ketogenic diet 
  • Antiseizure, anticancer, increased learning/​​memory, antianxiety effects
  • Increase in GABAergic tone (calming neurotransmitter)
• Clinical trials investigating ketone supplements for various conditions 
  • Rapid expansion of research in this area
  • Potential for ketones to become a widely studied and utilized supplement like creatine
    Ketone Supplements: Ester vs. Salt
• Ketone supplements can elevate ketones for 1 to 8 hours, depending on the formulation 
• Combining ketone salts with medium-​​chain triglycerides (MCT) can delay gastric absorption and sustain hyperketonemia over time
• Rapid spike in ketones can cause a release in insulin, which can shut down natural ketone production
• Gradual rise in ketones is more ideal for maintaining ketosis

Ketone Ester

• Beta-​​hydroxybutyrate ester quickly spikes ketone levels, but can also cause a drop in glucose levels
• Rapid elevation of ketones can produce a counterregulatory effect, releasing insulin and potentially affecting therapeutic management of conditions like cancer and seizures
• Monoester and diester have different effects on antiseizure activity; diester has a stronger antiseizure effect

Ketone Salt

• Ketone salts with electrolytes can delay gastric absorption, causing a more gradual rise in ketones
• Consuming a full packet of ketone salt can elevate ketone levels by about 1.5 millimolar without causing a significant insulin spike
• Ketone salts can be combined with a modified ketogenic diet for an optimized lifestyle and potential therapeutic benefits

Benefits of Elevated Ketones

• Ketones have a satiating effect on the brain, making it easier to adhere to calorie-​​restricted diets
• Elevated ketones can help maintain brain energy metabolism, preventing an energetic crisis during periods of low glucose
• Combining ketone supplements with a ketogenic diet may be beneficial for epilepsy, cancer, type 2 diabetes, and weight loss

Ketone Supplements and Seizures

• Acetoacetate and acetone have shown antiseizure effects in animal models
• The ketone diester elevates both beta-​​hydroxybutyrate and acetoacetate, providing a strong antiseizure effect
• Combining ketone ester with MCT can further elevate ketones and extend the sustainment of ketosis, potentially enhancing antiseizure effects
  Ketone Salts and Supplements
• Ketone salts mixed with MCT have favorable effects on glycemic regulation, antianxiety, and antiseizure 
• Ketone esters can cause metabolic acidosis when ketones get above 3 millimolar 
  • Better to keep exogenous ketones within an elevation of 1–3 millimolar
• Supplements beneficial with a ketogenic diet: 
  • Electrolytes
  • Creatine
  • Acetyl L‑carnitine
  • Taurine
  • Omega-​​3s (DHA, EPA)
  • Magnesium
  • Vitamin D
• Vitamin D levels can be affected by: 
  • Polymorphisms in vitamin D metabolism genes
  • Inaccurate concentrations in supplements
  • Skin type and sun exposure
• Prescription vitamin D is usually vitamin D2, which may have some drawbacks compared to vitamin D3 
  • Vitamin D3 can be obtained from lichen for vegetarians
    Ketones and Muscle Preservation
• Ketones have anti-​​catabolic effects, important for preserving muscle mass 
• Ketogenic diets are not optimal for building muscle mass but can help preserve muscle during calorie deficits
• Ketones can help prevent muscle loss during fasting and calorie deficit
• Ketones have anti-​​inflammatory effects that can help prevent muscle wasting associated with cachexia and aging

Intermittent Ketosis and Fasting

• Chronic ketosis may not be ideal for most people, unless managing a chronic disorder
• Intermittent fasting and relative changes in ketosis can provide benefits
• Fasting Mimicking Diet by Dr. Walter Longo can have long-​​lasting metabolic benefits

Ketogenic Diets and Exercise Performance

• In animal models, ketogenic diets have shown to improve running performance
• In humans, data on exercise performance while on a ketogenic diet is messy and hard to make sense of
• Effects on aerobic vs. anaerobic exercise performance may vary
  Ketones and Exercise Performance
• Small effect on aerobic performance 
• Strength performance effects still being studied
• Ketone salts with caffeine may be a powerful ergogenic aid
• Exogenous ketones may preserve performance resilience in extreme environments 
  • Hyperoxia and hypoxia
  • Military, space, and altitude settings

Ketones and Training

• Chronic use of exogenous ketones may facilitate adaptive response to exercise over time 
  • Suppressing inflammation and enhancing adaptive responses
• Train in a state of ketosis to induce metabolic adaptations 
  • Metabolic flexibility: train low (low glucose, low insulin), perform with mixed fuels (glucose, fatty acids, ketone bodies, lactate)
• Periodize training and nutrition for optimal performance

Ketones and Nervous System

• Ketogenic diets and ketosis have significant benefits for the brain and nervous system 
  • Epilepsy and other brain disorders
  • Preclinical studies show benefits in mice
• Dr. Eric Verdin’s study on cyclical ketogenic diet in mice 
  • Mice started midlife, showed benefits for brain health
  • Mice overeating on the ketogenic diet, which is unusual as it typically promotes satiety
    Effects of Ketogenic Diet on Rodents
• Health span and median lifespan improved 
• Older mice had better cognition than younger mice
• Results may be magnified in rodents, not always predictive for humans
• Different strains of rodents react differently to ketogenic diets
• Calorie restriction combined with ketogenic diet seems to be effective
• Suppression of spontaneous tumors observed in some studies

Rodent Research and Human Implications

• Rodent research is informative but not always predictive for humans
• Ketogenic diet and intermittent fasting may have positive effects on cognition and anxiety
• Caloric restriction and exercise can also lead to ketosis and improved cognitive function
• Time-​​restricted eating has been beneficial for some individuals
• Combining low carb, intermittent fasting, and ketogenic diet may have more benefits than chronic ketosis

Personal Experiences with Ketogenic Diet and Intermittent Fasting

• Anxiety levels noticeably lower on a ketogenic diet
• Improved cognition and calmness observed
• Time-​​restricted eating has been beneficial for some individuals
• Interest in incorporating a cyclical ketogenic diet with intermittent fasting and biomarker tracking
  Intermittent Fasting and Ketogenic Diet in Epilepsy and Neurodegenerative Disorders
• Intermittent fasting and ketogenic diet can help control seizures in some epilepsy patients 
  • Time-​​restricted feeding with a ketogenic diet can improve seizure control
  • Hormonal effects of intermittent fasting are replicated with the ketogenic diet
  • Hyperketonemia associated with both intermittent fasting and ketogenic diet have their own effects through beta-​​hydroxybutyrate and acetoacetate
• Ketogenic diet and ketone supplements may have potential benefits for neurodegenerative disorders like Parkinson’s and Alzheimer’s disease 
  • Different subtypes of Alzheimer’s disease may respond differently to ketogenic interventions
  • Ketogenic diet can alter brain metabolism and pharmacology, potentially benefiting various neurological disorders and even cancer
  • Clinical trials are needed to confirm these benefits and establish guidelines for prescribing ketogenic diets or supplements
• Metabolic psychiatry is exploring dietary interventions for a range of psychiatric disorders, including depression, bipolar disorder, and eating disorders 
  • Clinical trials are ongoing, but data is not yet sufficient to prescribe ketogenic diets or supplements for these conditions
• Anecdotal evidence suggests that ketone supplements may help alleviate migraines and tremors in some individuals 
  • More research is needed to confirm these effects and understand the underlying mechanisms
    Ketogenic Diet and Migraines
• Dr. Ileana Gross discovered that the ketogenic diet and ketone supplements helped manage her chronic migraines 
• Ketogenic diet for migraines likely works through multimodal mechanisms 
  • Increases GABAergic tone
  • Increases brain blood flow
  • Increases adenosine, a powerful vasodilator
• Fasting and exogenous ketones can help manage migraines and inflammation

Ketogenic Diet and Autoimmune Disease

• Dietary interventions can be powerful modulators of the immune system 
  • Suppressing inflammatory mediators (IL‑6, IL‑1 beta, TNF alpha)
  • Enhancing anti-​​cancer immunity
• Ketogenic diet can make the immune system more hyper-​​vigilant in detecting cancer cells
• Standard cancer treatments (chemotherapy and radiation) can be more effective in the context of a ketogenic diet 
  • Protects healthy cells
  • Augments immune system to attack cancer cells

Hyperbaric Oxygen Therapy and Cancer

• Dr. Dominic D’Agostino observed cancer cells exploding under hyperbaric oxygen 
  • Cancer cells have defective mitochondria, producing more superoxide anion when exposed to oxygen
  • Superoxide anion can be converted to hydrogen peroxide and more reactive intermediates, damaging membrane lipids and causing cell rupture
• This observation led to further research on targeting cancer cells and manipulating substrates with ketones and the ketogenic diet
  Cancer Cells and Ketogenic Diet
• Cancer cells are more heterogeneous than previously believed 
• Some cancers are very responsive to the ketogenic diet 
  • Brain tumors, aggressive solid tumors, endometrial cancers, certain GI cancers, and lung cancer
• Ketogenic diet’s therapeutic efficacy is through insulin suppression, limiting glucose availability, and elevating ketones 
  • Exogenous ketones can extend the life of animals with metastatic cancer
• Ketones may not be an ideal fuel for tumors 
  • Tumor cells die in the absence of glucose
  • Ketones may decrease proliferation by reducing hexokinase, a glycolytic enzyme
• Ketogenic diets can be optimized with plant fiber and phytonutrients for chemo prevention effects

Carnivore Diet

• A form of a ketogenic diet that can be beneficial for some people
• Concerns include elevated LDL and triglycerides
• May not be sustainable or optimal long-term
• Lack of fiber and phytonutrients in the diet 
  • Fiber is not necessary but is considered optimal for gut health
  • Butyrate from fiber is important for colonocyte health and gut microbiome
    Dietary Diversity and Adaptability
• Humans are omnivores and adaptable to various diets 
• Some populations thrive on limited diets (e.g., cornmeal, whale blubber)
• Dietary diversity may provide an array of nutrients

Carnivore Diet

• Beneficial for some, but suboptimal as a ketogenic diet
• Lack of empirical evidence supporting its benefits
• Some individuals thrive on it, correcting autoimmune disorders and achieving high physical performance
• Calorie intake still matters in carnivore diet

Intermittent Fasting and Exercise

• Small ketogenic breakfast, fasting through midday, and consuming most calories in the evening
• Resistance training and bodyweight exercises
• Farm work and outdoor activities for overall health

Heat Therapy

• Hot tub therapy can help lower blood pressure
• Hyperthermia has potential health benefits

Measuring Ketones

• Blood ketone measurements: best for starting a ketogenic diet
• Breath acetone measurements: best for fasting and weight loss
• Urine ketone strips: semi-​​quantitative, not very accurate
• Continuous glucose monitoring (CGM) can be used to monitor adherence to a ketogenic diet

Blood Glucose Levels as a Proxy for Ketosis

• CGM trace should be flat for those adhering to a ketogenic diet
• Blood glucose levels can be used to estimate ketosis, but individual levels may vary
  Sleep and Blood Glucose
• Disrupted and fragmented sleep can cause blood glucose levels to spike 
  • Example: Levels reaching 130–140 after only 4.5 hours of sleep
• Exercise can help negate glucose dysregulation caused by sleep disruption 
  • Example: Spin class leading to better glucose levels despite sleep disruption

Continuous Glucose Monitors (CGM)

• Wearing a CGM can help identify foods and portion sizes that work best for an individual
• Levels is a CGM company that offers coaching and nutritionist support 
  • Provides daily and weekly reports on glucose levels and metabolic scores
  • Can be engaged with as little or as much as desired

Surprising Foods Affecting Blood Glucose

• Cooked spinach causing a spike in blood glucose
• “Keto” labeled foods sometimes containing added sugars
• Collagen gummy chewables and sugar-​​free gummies causing glucose spikes
• Most bars marketed as keto-​​friendly are not truly ketogenic 
  • Keto Brick is an exception, with 90g of fat, 30g of protein, and minimal carbohydrates

Resources

• Ketonutrition​.org — Dom’s website and blog
• Metabolic Health Summit — Event happening May 5–8 in Santa Barbara, California
• Dom’s recommended supplements: 
  • Keto Start (exogenous ketone product)
  • Keto Brick (keto bar)
  • Keto Brains (coffee creamer with added nootropics)
• Dom is active on Twitter, Instagram, and Facebook, sharing new literature and research in the keto space