#023 Dominic D'Agostino, Ph.D. on Modified Atkins Diet, Ketosis, Supplemental Ketones and More
Dr. Dominic D'Agostino, an assistant professor at the University of South Florida, discusses nutritional ketosis, ketone supplementation, and their therapeutic and performance-enhancing effects. He highlights their potential for neurological disorders, cancer, and metabolic health, emphasizing the physiological adaptations and signaling roles of ketones.
Deep Dive Analysis
14 Topic Outline
Introduction to Dr. D'Agostino's Metabolic Research
Defining and Measuring Nutritional Ketosis
Dietary Strategies for Achieving Ketosis: Classical vs. Modified Atkins
Impact of High-Fat Diets on Gut Health
Physiological Adaptations to Keto-Adaptation
Ketones as a Superior Fuel and Reactive Oxygen Species Reduction
Brain Energy Metabolism and Ketone Utilization
Ketones, Blood Flow, and Alzheimer's Disease
Therapeutic Potential of Ketone Supplementation
Ketones and Cancer Treatment in Animal Models
Metformin's Role in Cancer Prevention and Longevity
Gluconeogenesis and Glucose Production in Ketosis
Glutamine's Dual Role in Cancer and Gut Health
Future of Ketone Supplements and Ketogenic Food Products
6 Key Concepts
Nutritional Ketosis
Nutritional ketosis is defined as achieving and sustaining blood ketone levels above 0.5 millimolar, ideally between 1 and 3 millimolar. This state is driven by the suppression of the hormone insulin, which in turn drives hepatic ketogenesis.
Classical Ketogenic Diet
This is a very strict diet, typically comprising 85-90% fat, 8-10% protein, and minimal carbohydrates. It was originally heavily based on dairy fat and used for drug-resistant epilepsy, but is challenging to follow due to its restrictive nature.
Modified Atkins Diet
A more liberal approach to the ketogenic diet, consisting of roughly 65-70% fat, 20-30% protein, and 5-10% carbohydrates. It has shown similar therapeutic potency to the classical ketogenic diet for drug-resistant epilepsy, making it more accessible.
Keto-adaptation
This is a physiological process where the body adapts to primarily using fatty acids and ketones for fuel instead of glucose. Over time, it leads to an upregulation of ketone transport and utilization mechanisms, as well as an increased oxidative capacity of cells.
Glucose Sparing
When the brain utilizes ketones as a primary energy source, it can 'spare' glucose, allowing it to be shunted into other metabolic pathways. This includes the pentose phosphate pathway, which is crucial for generating NADPH, important for glutathione recycling and dealing with stress.
Metabolic Theory of Cancer
This theory proposes that cancer originates from progressive damage to mitochondrial oxidative phosphorylation, leading to impaired energy status in the cell. This energetic crisis then triggers the nucleus to activate oncogenes, transforming a normal cell into a cancer cell with a Warburg (glycolytic) phenotype.
10 Questions Answered
Nutritional ketosis is defined as achieving and sustaining blood ketone levels above 0.5 millimolar, ideally between 1 and 3 millimolar, which can be measured using blood ketone devices.
A classical ketogenic diet is typically very high in fat (85-90%), moderate to low in protein (8-10%), and very low in carbohydrates, often based on dairy fat.
The Modified Atkins Diet is more liberal, consisting of roughly 65-70% fat, 20-30% protein, and 5-10% carbohydrates, making it more accessible while retaining therapeutic potency.
While high-fat diets in animal studies can induce endotoxin release, a 'well-formulated' ketogenic diet with diverse raw vegetables can actually improve gut health and microbiome diversity by feeding different bacteria.
Ketones, particularly beta-hydroxybutyrate, lead to oxidized ubiquinone (Q), making it less available to react with molecular oxygen in the electron transport chain, thus producing less superoxide anion.
In contexts like aging, traumatic brain injury, pathology, or stress (e.g., hypoglycemia), the brain may prefer ketones due to impaired brain glucose metabolism, such as issues with GLUT3 transporters or pyruvate dehydrogenase complex.
Yes, studies in animal models have shown that ketone supplementation can prevent CNS oxygen toxicity and significantly increase survival time in metastatic cancer models, even on a high-carbohydrate diet.
Metformin, a diabetes drug, has been shown in retrospective studies to reduce the risk of certain cancers (e.g., pancreatic cancer by 62% in type 2 diabetics) and is being studied as a potential preventative therapy due to its effects on AMP kinase, mTOR, and insulin signaling.
For GI cancers and liver cancer, it is advisable to avoid or minimize glutamine supplementation and high glutamine-containing foods, as these cells may utilize glutamine for growth. For other cancers, if systemic treatments impair gut function, a small amount of glutamine might be helpful for gut repair.
Yes, ketones are considered anti-catabolic and protein-sparing, meaning they help protect gluconeogenic amino acids and skeletal muscle from being degraded, especially when ample fat is consumed to provide sufficient fuel.
28 Actionable Insights
1. Measure Blood Ketones
To confirm you are in a state of ketosis, measure your blood ketones and aim for levels between 1 and 3 millimolar, with a minimum of 0.5 millimolar. This helps verify if a ketogenic diet or intervention is effective.
2. Prioritize Diverse Raw Vegetables
To optimize gut health and microbiome diversity on a ketogenic diet, ensure you include a diverse variety of raw vegetables as carbohydrate sources.
3. Optimize Carb & Fat Sources
Beyond macronutrient ratios, optimize your ketogenic diet by focusing on the sources of fats, the type of protein, and the quality and type of carbohydrates, as these factors are crucial for individual health and gut microbiome diversity.
4. Avoid High Protein on Keto
When following a ketogenic diet, ensure your protein intake is moderate to low, not high, as many people mistakenly consume a high-protein, moderate-fat diet instead of a true ketogenic diet. High protein can hinder ketosis.
5. Consult a Savvy Dietitian
If you plan to try a ketogenic diet, start by consulting a savvy dietitian who can tailor and tweak the diet to your specific needs, as their experience is invaluable.
6. Consider Modified Atkins Diet
For a more accessible approach to therapeutic ketosis, consider the Modified Atkins Diet, which is 65-70% fat, 20-30% protein, and 5-10% carbohydrates, allowing for more protein and incorporating medium-chain fatty acids while maintaining therapeutic potency.
7. Personalize Ketogenic Diet
Tailor your ketogenic diet to your individual sensitivities, such as avoiding dairy or nuts if you have allergies or intolerances, to optimize your personal health and adherence.
8. Include Liberal Vegetables on Keto
To support gut health while on a ketogenic diet, ensure your diet includes a liberal amount of vegetables, as this has been associated with better gut health for some individuals.
9. Use Vegetables to Slow Digestion
Incorporate vegetables into your ketogenic diet as carriers for fat, as they help slow protein digestion, minimize insulin spikes, and aid in maintaining ketosis.
10. Use MCT Powder for Mild Ketosis
To achieve a mild state of ketosis with better GI tolerance than liquid MCT oil, use MCT powder, consuming 4-8 scoops daily mixed with water, coffee, or tea.
11. Prioritize Whole Foods with Ketones
Even when using ketone supplements, prioritize a whole-food diet free of refined crap and processed foods, as a poor diet will significantly diminish the benefits of ketones.
12. Cycle Metabolic Strategies for Flexibility
To promote metabolic flexibility and enhance the long-term effectiveness of interventions, cycle between different dietary strategies like a paleo diet, a low-carb ketogenic diet, and intermittent fasting on occasional days, rather than strictly adhering to one continuously.
13. Maintain Ketosis to Preserve Muscle
Maintain a state of ketosis to leverage its anti-catabolic and protein-sparing effects, which help protect gluconeogenic amino acids and skeletal muscle from degradation.
14. Ensure Ample Fat on Ketogenic Diet
When on a ketogenic diet, ensure you consume ample amounts of fat, as insufficient fat intake can lead to a more catabolic state.
15. Use Ketones for Appetite Control
Utilize ketones to help control appetite, as they have a satiating effect by sending energy to the brain and can shut off hypoglycemic triggers that lead to food cravings or binges.
16. Consider Ketogenic Intermittent Fasting
For potential cancer prevention or post-treatment care, consider a ketogenic intermittent fasting protocol where you consume ketogenic fats and ketone supplements for 20 hours, followed by a four-hour window to eat a well-balanced ketogenic meal rich in vegetables and healthy fats and protein.
17. Metformin for Cancer Prevention (Consult Doctor)
Discuss with your doctor the potential of metformin as a preventative therapy, especially if you are at risk for certain cancers like pancreatic cancer, given studies showing a significant reduction in risk for type 2 diabetics taking the drug.
18. Monitor B12 with Metformin
If taking metformin, be aware of potential vitamin B12 deficiency and consider supplementing with a sublingual form or B12 injections, especially as B12 absorption decreases with age.
19. Enhance Drug Delivery with Ketosis
If taking drugs that need to cross the blood-brain barrier (e.g., chemotherapeutics), consider inducing ketosis through fasting or a ketogenic diet, as this may increase blood-brain barrier permeability and facilitate faster drug transport.
20. Avoid Glutamine for GI/Liver Cancer
If you have gastrointestinal or liver cancer, avoid supplementing with glutamine and minimize high glutamine-containing foods, as these cancers may utilize glutamine for growth.
21. Glutamine for Impaired GI Function (Non-GI Cancer)
If you have impaired GI function due to systemic treatments (e.g., for a brain tumor) and do not have GI or liver cancer, a small amount (5-10 grams) of oral glutamine may be helpful to repair your gut.
22. Lower Glutamine on Ketogenic Diet
A classical ketogenic diet (low to moderate protein) can help lower blood glutamine levels, which may be beneficial in certain cancer contexts.
23. Select Low-Glutamine Protein Sources
To further suppress glutamine levels, select protein food sources that are lower in glutamine and consider avoiding glutamine supplementation, opting instead for supplements high in essential amino acids (excluding glutamine).
24. Lauric Acid Suppresses Hunger
Consider consuming lauric acid (C12) as it has been shown to suppress ghrelin, a hunger hormone, in the gut.
25. Classical Ketogenic Diet Ratios
To achieve nutritional ketosis, a classical ketogenic diet typically involves a 4:1 or 3:1 ratio of fat to combined carbohydrates and protein, often translating to 85-90% fat, 8-10% protein, and minimal carbohydrates, historically relying heavily on dairy fat.
26. Ketone Supplements for Cancer (Research)
Research suggests that ketone supplementation, even on a high-carbohydrate diet, can reduce tumor growth and proliferation and increase survival time in aggressive metastatic cancer models, indicating potential anti-cancer effects.
27. Avoid Antioxidant Supplements for Cancer (Research)
Studies suggest that giving mice supplemental vitamin E or N-acetylcysteine (NAC), which potently sequester reactive oxygen species, can actually allow tumors to grow faster, implying caution with antioxidants in cancer contexts.
28. Ketone Esters for Potent Ketosis (Future)
For a powerful form of exogenous ketones, look for ketone esters (currently in development for human use) which have shown significant effects, such as preventing CNS oxygen toxicity.
8 Key Quotes
Pretty much every neurological disorder is some way linked to a metabolic dysregulation.
Dr. Dominic D'Agostino
Ketones are more than just the metabolite. They're more than just an energy metabolite the brain can use, but they are... metabolites, especially beta-hydroxybutyrate, are very powerful signaling molecules.
Dr. Dominic D'Agostino
The ketogenic diet is not a high-protein diet. It's actually moderate to low-protein diet, and most people don't understand that.
Dr. Dominic D'Agostino
If Q is oxidized, then you have less availability for that electron to react with molecular oxygen in the metabolic pathway. So, you would produce less superoxide anion, which is your precursor to more reactive oxygen species.
Dr. Dominic D'Agostino
The stability of the nuclear genome is tightly regulated to the energetic state of the cell.
Dr. Dominic D'Agostino
Ketones, we know undoubtedly they have anti-cancer effects, and it could be maybe through their expression of their gene expression as a histone deacetylase inhibitor.
Dr. Dominic D'Agostino
Metabolic interventions tend to work best when you cycle them, I think.
Dr. Dominic D'Agostino
If you're in a state of ketosis, you're protecting gluconeogenic amino acids and skeletal muscle from being degraded.
Dr. Dominic D'Agostino
2 Protocols
Modified Atkins Diet for Therapeutic Ketosis
Dr. Dominic D'Agostino (referencing Eric Kosoff's work)- Consume roughly 65-70% of total calories from fat.
- Consume about 20-30% of total calories from protein.
- Limit carbohydrates to no more than 5-10% of total calories.
- Incorporate medium-chain fatty acids into the diet.
- Optimize the diversity of carbohydrate sources, primarily from raw vegetables, to support gut health.
Ketogenic Intermittent Fasting (Proposed)
Dr. Dominic D'Agostino- Consume ketogenic fats and ketone supplements throughout a 20-hour fasting window.
- Eat a well-balanced ketogenic meal, rich in vegetables, high in fats, and protein, within a 4-hour eating window.