#074 Dr. Dominic D'Agostino on Developing a Well-Designed Ketogenic Diet and Harnessing Its Benefits
Dr. Dominic D'Agostino, an Associate Professor at the University of South Florida and research scientist, discusses the science of ketogenic diets, ketosis, and ketone supplements. He covers practical tips for implementation, monitoring biomarkers, and their potential therapeutic applications for metabolic health, neurological disorders, and exercise performance.
Deep Dive Analysis
17 Topic Outline
Introduction to Dr. Dominic D'Agostino and Ketogenesis
Defining Ketogenic Diets and Variations
Transitioning to a Ketogenic Lifestyle
Importance of Fiber and Fat Types in Ketogenic Diets
Ketogenic Diet Considerations for ApoE4 and Biomarker Monitoring
Understanding Exogenous Ketones: Esters, Salts, and MCTs
Physiological Effects and Optimal Dosing of Ketone Supplements
Anti-Catabolic Effects of Ketones on Muscle Mass
Ketones and Exercise Performance in Various Environments
Cyclical Ketogenic Diets and Brain Health in Rodent Models
Overlap Between Ketosis, Fasting, and Brain Health
Ketogenic Diets for Neurodegenerative Disorders
Ketogenic Diets and Ketone Supplements for Migraines
Ketogenic Diets and Autoimmune Disease/Cancer
Carnivore Diet: Benefits, Drawbacks, and Optimal Considerations
Dr. D'Agostino's Personal Lifestyle Habits
Measuring Ketones and Glucose
7 Key Concepts
Ketogenic Diet
A ketogenic diet is a dietary therapy uniquely defined by an objective biomarker: elevated ketones in the blood, urine, or breath. It works by suppressing insulin, depleting liver glycogen, and accelerating the beta-oxidation of fatty acids to produce ketone bodies.
Metabolic Switching
This refers to the physiological transition into ketosis, where the body shifts from primarily oxidizing glucose for energy to utilizing fats and ketones. Fasting can help facilitate this switch, and a gradual reduction in carbohydrates can ease the transition for those new to a ketogenic diet.
Exogenous Ketones
These are calorie-containing molecules, like ketone esters or salts, that are consumed to directly elevate ketone bodies (beta-hydroxybutyrate and acetoacetate) in the blood and tissues, mimicking some effects of a ketogenic diet without strict carbohydrate restriction.
Ketone Esters
A type of exogenous ketone, often 1,3-butanediol bound to beta-hydroxybutyrate or acetoacetate. They typically cause a very rapid and high spike in blood ketone levels, which can sometimes lead to a counter-regulatory insulin release and a subsequent drop in glucose.
Ketone Salts
A type of exogenous ketone where beta-hydroxybutyrate is bound to electrolytes like sodium, potassium, calcium, and magnesium. These tend to cause a slower, more sustained elevation of blood ketones compared to esters, partly due to the electrolytes delaying gastric absorption.
Glucose Ketone Index (GKI)
A ratio calculated by dividing blood glucose (in millimolar) by blood ketones (in millimolar). It is used as a biomarker to assess the depth of ketosis, with a GKI of one or lower often associated with maximizing autophagy and other therapeutic benefits.
Metabolic Flexibility
The body's ability to efficiently switch between different fuel sources, such as glucose, fatty acids, and ketones, for energy. This can be enhanced by training in a low-glucose, low-insulin state (e.g., semi-fasted) to induce metabolic adaptations.
11 Questions Answered
A ketogenic diet is defined by elevated ketone levels. Variations range from a classical 4:1 ratio (90% fat, 1 part protein/carbs) used for pediatric epilepsy, to more liberal modified Atkins or low glycemic index therapies (1:1 ratio) that produce milder ketosis but still offer therapeutic effects.
For lifestyle purposes, it's recommended to ease into it by gradually titrating carbohydrates down over four to six weeks. This approach improves compliance, adherence, and results, and reduces side effects like sleep disruption or lipid abnormalities that can occur with an abrupt start.
It's important to monitor glucose response and check for hypoglycemia. For ApoE4 individuals, a high-fat diet is not ideal; a moderate approach with restricted carbohydrates, plenty of fiber and phytonutrients, and monounsaturated fats is suggested, potentially with ketone supplementation.
Ketone esters typically cause a rapid and high spike in blood ketones, which can trigger an insulin response. Ketone salts, bound to electrolytes, tend to produce a slower, more sustained elevation of ketones, and the electrolytes themselves can delay gastric absorption.
An elevation of blood ketones between 1 to 3 millimolar is considered optimal for most people. Higher levels, especially from large doses of ketone esters, can lead to a metabolic acidosis (pH drop) and an undesirable insulin release.
Ketones likely have a small positive effect on aerobic performance and can help preserve performance resilience in extreme environments like hyperoxia or hypoxia. Chronically using exogenous ketones may also facilitate adaptive responses to exercise over time by suppressing inflammation.
Preclinical rodent studies have shown that a cyclical ketogenic diet can improve healthspan and cognitive function, with older mice exhibiting better cognition than younger mice. While rodent models are informative, human translation needs further validation through clinical trials.
Both intermittent fasting and ketogenic diets suppress insulin and IGF-1, lower mTOR, and activate AMP kinase. Additionally, the hyperketonemia produced by both approaches provides alternative energy and acts as a signaling molecule, mediating anti-inflammatory and epigenetic effects, and boosting factors like BDNF.
Preliminary clinical evidence and anecdotal reports suggest that ketogenic diets and supplemental ketones may improve some types of migraines. This is thought to occur through multimodal mechanisms, including increased GABAergic tone, improved brain blood flow (possibly via adenosine), and anti-inflammatory effects.
For initial assessment, urine strips are semi-quantitative and can indicate ketosis. For more accuracy, a blood ketone meter (like Keto-Mojo) is good. For fat loss, a breath acetone meter (like Readout Health Biosense) is recommended as breath acetone correlates well with fat oxidation and is more stable than blood beta-hydroxybutyrate during activity.
Sleep disruption can significantly impact blood glucose levels, leading to unexpected spikes, even in individuals on a ketogenic diet. This was observed through continuous glucose monitoring, showing glucose levels rising to postprandial-like levels during nights with fragmented sleep.
64 Actionable Insights
1. Prioritize Muscle Mass for Healthy Aging
Focus on building and preserving as much muscle mass as possible, as it is considered the most important factor for healthy aging.
2. Practice Cyclical Ketosis and Fasting
Avoid chronic ketosis or daily intermittent fasting unless managing a specific disorder; instead, practice cyclical ketosis or intermittent fasting (e.g., 2-3 times a week or a 5-day fasting-mimicking diet monthly) to maximize benefits and prevent losing too much weight or blunting adaptations.
3. Combine Modified Keto with Fasting
Combine a modified ketogenic diet with intermittent fasting to leverage synergistic benefits from insulin and IGF-1 suppression, AMP kinase activation, and the drug-like signaling effects of ketones (e.g., anti-inflammation, epigenetic changes, BDNF induction).
4. Prioritize Calorie Deficit for Weight Loss
To lose weight and sustain it, achieve and maintain a protracted calorie deficit, recognizing that calories absolutely matter, even on a ketogenic diet.
5. Acknowledge Calories Matter on Keto
Understand that calories absolutely matter, even on a ketogenic diet, and do not disregard calorie counting, especially when aiming for weight loss or specific metabolic goals.
6. Ensure Micronutrients & Fiber on Keto
Prioritize consuming lots of fiber and phytonutrients, and ensure adequate micronutrient intake (e.g., selenium) through diet or appropriate supplementation to prevent deficiencies and support overall health on a ketogenic diet.
7. Optimize Keto with Phytonutrients & Fiber
Enhance the anti-carcinogenic potential of a ketogenic diet by incorporating plant fiber and specific phytonutrients like curcumin, turmeric, and EGCG.
8. Incorporate Raw Fibrous Vegetables
Consume leafy greens raw rather than cooked on a ketogenic diet, as cooking ruptures cell walls, making carbohydrates more accessible and increasing their glycemic impact.
9. Maintain Insulin Suppression for Ketosis
Continuously suppress insulin and insulin signaling to effectively maintain a state of ketosis, which is crucial for therapeutic goals like managing cancer or seizures.
10. Gradually Transition to Ketogenic Diet
For better compliance and to avoid side effects like sleep disruption or lipid abnormalities, gradually titrate down carbohydrate intake over four to six weeks when transitioning to a ketogenic diet.
11. Seek Medical Supervision for Therapeutic Keto
If using a ketogenic diet to manage a metabolically linked or brain disorder like epilepsy, start with a clinical ketogenic diet under the supervision of a registered dietitian and a neurological team.
12. Monitor Biomarkers During Keto Transition
When transitioning to a ketogenic diet for general health, gradually reduce carbohydrates, track and monitor progress, and get blood work (including glucose response) at the 4-6 week mark to check for hypoglycemia or other issues.
13. Confirm Ketosis with Objective Biomarkers
To confirm you are on a ketogenic diet, measure your ketone levels in blood, urine, or breath, as hyperketonemia (elevated ketones) is the objective biomarker defining the diet.
14. Choose Ketogenic Diet Variation
Select a ketogenic diet variation based on your goals, ranging from a classical 4:1 ratio (90% fat) for therapeutic purposes to a modified Atkins or low glycemic index therapy (1:1 ratio) for a milder, lifestyle-oriented ketosis.
15. Modify Keto for ApoE4 Carriers
For ApoE4 carriers, adopt a moderate-fat, moderate-protein, plant-based fiber diet, focusing on monounsaturated fats and MCTs over heavy saturated fats, and consider supplementing with exogenous ketones.
16. Adopt Moderate Mediterranean-Keto Diet
Consider a moderate Mediterranean-style low-carb/ketogenic diet, emphasizing monounsaturated fats, omega-3 fatty acids, and MCT oils, while limiting heavy saturated fats, especially if you are an ApoE4 carrier.
17. Supplement Carnitine on Keto Diet
Supplement with carnitine on a ketogenic diet, as fat oxidation can lead to carnitine deficiency, and it can also help boost ketosis.
18. Consider Multivitamin on Keto Diet
Take a standard multivitamin to ensure adequate micronutrient intake, especially if your ketogenic diet formulation doesn’t consistently provide all necessary nutrients.
19. Consume Nutrient-Dense Whole Foods
Incorporate nutrient-dense foods like eggs, sardines, fish, and oysters into your ketogenic diet to obtain essential nutrition and prevent potential deficiencies.
20. Supplement Magnesium for Keto
Supplement with magnesium, potentially in multiple forms like magnesium threonate, as it is beneficial with a ketogenic diet and can help maintain adequate blood levels.
21. Monitor Vitamin D & Supplement Effectively
Regularly monitor your vitamin D levels, as even with sun exposure and supplementation, levels can be low; ensure your chosen supplement brand is effective, potentially by checking third-party testing.
22. Consider Genetic Factors for Vitamin D
If you have consistently low vitamin D levels despite supplementation and sun exposure, consider genetic testing for SNPs that affect vitamin D3 metabolism, as you may require a significantly higher dose.
23. Use Keto to Preserve Muscle in Deficit
While not optimal for maximizing muscle size, ketogenic diets are an ideal strategy to preserve muscle mass during a calorie deficit, while also improving metabolic parameters like glycemia and hyperinsulinemia.
24. Elevate Ketones During Calorie Restriction
Elevate ketones during calorie restriction or an energy deficit to provide better fuel flow to the brain, making the diet more tolerable and sustainable by preventing painful hypoglycemia.
25. Use Ketones for Satiety and Weight Loss
Leverage the satiating effect of ketones, which provide alternative energy to the brain during low glucose, to reduce hunger signals and support weight loss.
26. Optimize Lifestyle Keto with Supplements
For an optimized ketogenic lifestyle, follow a more liberal ketogenic diet (e.g., modified Atkins or low glycemic index therapy) and supplement with exogenous ketones.
27. Prefer Electrolyte-Bound Ketones
Prefer ketone supplements where beta-hydroxybutyrate is ionically bound to electrolytes, as they provide needed minerals and avoid the potential liver enzyme elevation seen with high doses of 1,3-butanediol ketone esters.
28. Maintain Optimal Exogenous Ketone Levels
Aim to keep exogenous ketone levels within an optimal range of 1 to 3 millimolar, unless managing specific severe conditions like epilepsy or glucose transporter type 1 deficiency syndrome where higher levels may be beneficial.
29. Spread Ketone Supplement Doses
If managing conditions like type 2 diabetes, Alzheimer’s, or cancer, spread out ketone supplement doses rather than taking large single boluses.
30. Avoid Rapid Ketone Spikes
To prevent a counter-regulatory insulin release that can shut down natural ketone production, avoid consuming large doses of ketone esters on an empty stomach, which cause rapid, high spikes in ketones.
31. Combine Ketone Salts with MCT
To achieve a slower, more sustained elevation of blood ketones, combine ketone salts with medium-chain triglycerides (MCTs), as MCTs delay gastric absorption.
32. Adjust Ketone Supplement Timing
To control the duration of elevated ketones (1-8 hours), adjust whether you take ketone supplements on an empty stomach, with food, or combine different formulations like ketone esters with electrolyte salts.
33. Use Fasting to Initiate Ketosis
Incorporate fasting to speed up metabolic switching, facilitating the transition into ketosis from primarily using glucose to utilizing fat and ketones.
34. Combine Fat and Fiber with Protein
To prevent being kicked out of ketosis by an insulin response from protein, incorporate fat and fiber with your meals, especially at the beginning, to attenuate insulin release.
35. Optimize Food Order for Glycemic Response
Use a continuous glucose monitor to observe how the order and combination of foods impact your glycemic response, and adjust to attenuate insulin release.
36. Construct a Ketogenic Salad
Create a ketogenic salad with fatty fish (e.g., salmon), raw leafy greens (arugula, spinach, romaine), ample extra virgin olive oil, MCT oil, and a small amount of nuts like walnuts.
37. Train Under Low-Carb Conditions
When following a low-carbohydrate or ketogenic diet, train under those conditions to induce metabolic adaptations, enabling your body to perform and maintain performance with insulin suppression and low glucose availability.
38. Develop Metabolic Flexibility
Practice ’train low’ (exercising in a semi-fasted state with low glucose and insulin) to induce metabolic adaptations and flexibility, allowing you to optimally use various fuel sources and strategically reintroduce carbohydrates for peak performance during events.
39. Methodically Experiment with Diet/Supplements
Do not radically change your dietary or supplement approach just before an event; instead, experiment methodically with new strategies like MCTs and ketone esters well in advance.
40. Combine Ketones, Caffeine, Electrolytes
Consider combining ketones, caffeine, and electrolytes as a potentially powerful ergogenic aid to enhance exercise performance, especially in strength training.
41. Use Ketones in Extreme Environments
Utilize exogenous ketones to preserve performance resilience in extreme environments like hyperoxia or hypoxia, as they can provide an alternative fuel source when carbohydrate metabolism is impaired.
42. Incorporate Daily Exercise & Resistance
Engage in some form of exercise daily, including outdoor activity and resistance training (at least twice, ideally four times a week), with bodyweight exercises like chin-ups, push-ups, and dips being effective for busy schedules.
43. Practice Hot Tub Heat Therapy
Regularly use hot tub heat therapy (105-110°F for 15 minutes to raise core temperature to ~102°F) to significantly lower blood pressure and improve cardiovascular health.
44. Use High-Intensity Exercise for Glucose
Engage in high-intensity exercise, such as an hour-long spin class, to help negate glucose dysregulation, even during periods of sleep disruption or other stressors.
45. Target GKI of One for Autophagy
Aim to achieve and sustain a Glucose Ketone Index (glucose over ketones in millimolar concentration) of one for 24 hours, as this is believed to induce and potentially maximize autophagy, often achievable with a 72-hour fast.
46. Use Breath Acetone for Fat Loss
For monitoring fat loss, use a breath acetone meter, as breath acetone levels are a stable and better correlate of fat oxidation compared to blood beta-hydroxybutyrate, which can fluctuate with activity and fuel utilization.
47. Choose Breath Acetone Meter
For convenient and cost-effective ketone monitoring, especially for fat loss and fasting, use a breath acetone meter like the Readout Health Biosense device, as it avoids expensive strips and finger pricks.
48. Use Urine Strips, then Blood Meter
When starting a ketogenic diet, initially use semi-quantitative urine ketone strips to confirm ketosis, then invest in a more accurate blood ketone meter like the Keto-Mojo device for precise measurements.
49. Use CGM for Keto Adherence
Utilize a Continuous Glucose Monitor (CGM) to assess adherence to a ketogenic diet, as a flat glucose trace indicates proper adherence, while large excursions suggest otherwise.
50. Scrutinize ‘Keto’ Labeled Products
Be highly skeptical and scrutinize the ingredients of products labeled ‘keto,’ as many contain hidden sugars or ingredients that can significantly spike blood glucose and kick you out of ketosis.
51. Choose Keto Brick for True Keto Bar
For a truly ketogenic bar, consider Keto Brick, which provides 90 grams of fat, 20-30 grams of protein, minimal carbohydrates, and 1000 calories, unlike many misleading ‘keto’ labeled products.
52. Consider Specific Ketogenic Supplements
For daily ketogenic supplementation, consider Keto Start (exogenous ketones), Keto Brick (ketogenic bar), and Keto Brains (coffee creamer with alpha-GPC, theanine, lion’s mane, and C8).
53. Consider Cyclical Keto for Brain Health
Based on rodent studies showing improved healthspan, cognition, and suppression of spontaneous tumors, consider implementing a cyclical ketogenic diet, potentially combined with calorie restriction, for brain health and anti-aging benefits.
54. Screen for Metabolic Phenotype in Alzheimer’s
If considering a ketogenic diet for Alzheimer’s disease, screen for a metabolic phenotype using an FTG PET scan; if glucose hypometabolism is observed, a metabolic intervention like a ketogenic diet may be a beneficial approach.
55. Use Keto/Ketone Supplements for Migraines
Consider using a ketogenic diet or ketone supplements to manage chronic migraines, as they have been shown to help by potentially increasing GABAergic tone, brain blood flow, and reducing neuroinflammation.
56. Use Fasting/Ketones for Acute Inflammation
Consider acute fasting or using ketone esters/salts to mitigate inflammatory cascades associated with conditions like shingles or herpes simplex, potentially stopping episodes.
57. Change Ketone Supplement if Headaches
If you experience headaches from a ketone supplement, change the brand or type, as it could indicate issues with electrolytes, contaminants, purity, potency, or gut tolerability.
58. Enhance Anti-Cancer Immunity with Keto
Follow a ketogenic diet to augment the immune system, making it more hypervigilant and enhancing anti-cancer immunity.
59. Adopt Gradual Cancer Therapy Approaches
When using therapies that kill cancer cells, such as ketogenic diets, metabolic drugs, or hyperbaric oxygen therapy, adopt a gradual approach to avoid adverse effects like tumor lysis syndrome.
60. Utilize Keto for Cancer via Insulin
For cancer therapy, use a ketogenic diet primarily for its efficacy in suppressing insulin and the insulin pathway, limiting glucose availability to cancer cells, rather than just relying on hyperketonemia.
61. Deprive Cancer Cells of Glucose
To target aggressive, glycolytic cancer cells, limit glucose availability, as these cells primarily rely on fermentable fuels and may not be able to use ketones as an energy source due to damaged mitochondria.
62. Monitor Biomarkers on Carnivore Diet
If following a carnivore diet, monitor biomarkers like LDL and triglycerides, as they may elevate; consider adding fish, omega-3 fats, and plants back into your diet if blood work is concerning.
63. Create Calorie Deficit on Carnivore Diet
If following a carnivore diet, ensure you are creating a calorie deficit for potential benefits, as the amount and type of meat consumed can significantly impact results.
64. Include Fiber for Optimal Health
While not strictly necessary for survival, include fiber in your diet for optimal health, as excluding it entirely may not be beneficial given the strong data supporting its positive effects.
7 Key Quotes
A ketogenic diet is unique from a dietary therapy point of view in that it's the only diet that we know of that is defined by an objective biomarker. So that's ketones.
Dr. Dominic D'Agostino
If you are not in a state of hyperketonemia, elevated ketones, you're technically not on a ketogenic diet.
Dr. Dominic D'Agostino
Muscle mass is probably the most important factor for healthy aging. And focusing on building as much muscle as possible I think is super important and preserving that muscle with time.
Dr. Dominic D'Agostino
The fact that we're able to make ketones from fatty acids as a water-soluble fat molecule that could cross the blood-brain barrier, that actually becomes our safeguard to catabolic processes that would cause us to waste away.
Dr. Dominic D'Agostino
I think chronic ketosis is probably not natural or not ideal for most people, unless you're managing a chronic disorder that's responsive to chronic ketosis.
Dr. Dominic D'Agostino
I think the real benefit of ketones are not... I'm talking about this in the response... to an acute setting. Like consume ketones, go exercise, see what happens, right? ... Where I think exogenous ketones help, will help... is used chronically as an adaptive response.
Dr. Dominic D'Agostino
I think humans are omnivores and they're incredibly adaptable to any kind of diet... The question is what is optimal? Should we even be eating such a huge diversity of things? And I think that could be beneficial.
Dr. Dominic D'Agostino
2 Protocols
Gradual Transition to Ketogenic Diet (Lifestyle)
Dr. Dominic D'Agostino- Titrate carbohydrates down over a period of four to six weeks.
- Start by cutting daily carbohydrate intake in half or by two-thirds.
- Continue reducing carbohydrates to 100g, then 75g, then 50g over the transition period.
- Monitor blood work at the four- to six-week mark to assess glucose response and other biomarkers.
Dr. D'Agostino's Daily Supplement Regimen
Dr. Dominic D'Agostino- Take a small dose of ketone salts in the morning, combined with creatine, acetyl L-carnitine, and taurine.
- Take additional ketone salts midday as a 'pick-me-up' (e.g., two-thirds of a packet).
- Supplement with omega-3 fatty acids (DHA, EPA).
- Supplement with magnesium (e.g., magnesium threonate or a multi-form product).
- Supplement with Vitamin D (e.g., 5,000 IUs daily, after confirming levels).