How should someone new to ketogenic dieting approach carbohydrate restriction?

For those not using it for a specific disorder, a gradual transition over 4-6 weeks is recommended. Start by halving or two-thirds reducing carbohydrates, then titrating down to 50 grams. This eases the metabolic switch, improves adherence, and mitigates side effects like sleep disruption, lipid abnormalities, and sudden LDL spikes often associated with rapid initiation.

Why is fiber important in a ketogenic diet?

Fiber, especially from raw leafy greens, is crucial for improving digestion, protein assimilation, and enhancing gut microbiome diversity. It slows down nutrient absorption, moderates glycemic response, and contributes to the production of beneficial short-chain fatty acids like butyrate, which fuels colonocytes.

Are there any contraindications or special considerations for ketogenic diets, especially for APOE4 carriers?

Yes, inborn errors of metabolism like carnitine transferase deficiency (CPT1) are contraindicated and can be life-threatening. For APOE4 carriers, a high-fat, extremely high-saturated-fat diet is generally not ideal. A more moderate approach with restricted carbohydrates, ample fiber, phytonutrients, monounsaturated fats, and omega-3s, potentially supplemented with exogenous ketones, is suggested.

What are the different types of exogenous ketone supplements and their effects?

Exogenous ketones include ketone esters, ketone salts, and MCT oil. Ketone esters can cause a rapid, high spike in ketones but may also trigger an insulin release and metabolic acidosis at large doses. Ketone salts often include electrolytes and, especially when combined with MCTs, provide a slower, more sustained elevation of ketones, reducing the insulin response and maintaining longer-term hyperketonemia.

How do ketones contribute to satiety and weight loss?

Ketones serve as an alternative energy source for the brain. When circulating ketone levels are elevated, the brain doesn't experience an energetic crisis from low glucose, thus reducing hunger signals. This satiating effect makes ketogenic diets and ketone supplementation particularly beneficial for adhering to and sustaining a calorie deficit for weight loss, as it prevents the hunger typically associated with low-calorie, low-glucose diets.

What supplements are recommended to support a ketogenic diet?

Omega-3 fatty acids (DHA, EPA), Carnitine (due to fat oxidation), Magnesium (e.g., Magnesium Threonate or a multi-form product), and Vitamin D are important. A quality multivitamin can help, but ensuring adequate intake of selenium (found in eggs, sardines, oysters) is crucial to prevent deficiencies like cardiomyopathy.

What are the distinct effects of Beta-Hydroxybutyrate (BHB) vs. Acetoacetate?

BHB has epigenetic effects, inhibiting histone deacetylase and directly interacting with histones to cause modifications. Acetoacetate, on the other hand, stimulates skeletal muscle regeneration through mechanisms involving Irk, Mech, and Cyclin D. Both contribute to anti-catabolic effects, reducing alanine liberation and preserving branched-chain amino acids during energy deficits.

How do ketones affect exercise performance?

In animal models, ketogenic diets improve aerobic endurance. In humans, data is mixed but ketones (especially with caffeine and electrolytes) may offer a small boost. They truly shine in extreme environments like hyperoxia or hypoxia by preserving neurological function. Chronic ketone use may also suppress inflammation, enhancing adaptive responses to exercise over time.

What is metabolic flexibility, and how is it achieved?

Metabolic flexibility is the body's ability to efficiently switch between different fuel sources (glucose, fatty acids, ketones, lactate). It's achieved by 'training low'—exercising in a semi-fasted state with low glucose and insulin—to induce metabolic adaptations. This allows for optimal fuel utilization in high-performance situations, where carbohydrates can then be strategically titrated back in.

What is the overlap between ketogenic diets and intermittent fasting?

Both ketogenic diets and intermittent fasting work by suppressing insulin and IGF-1, while activating AMPK and downregulating mTOR. They both lead to hyperketonemia, which provides alternative energy and acts as a signaling molecule for anti-inflammatory and epigenetic effects (like Histone Deacetylase inhibition) and BDNF production. The hormonal and ketone-mediated effects are largely synergistic.

Can ketogenic diets treat neurodegenerative disorders like Parkinson's and Alzheimer's?

Research suggests that ketogenic diets show promise, particularly for patients with a metabolic phenotype of Alzheimer's. While anecdotal evidence, like Dr. Mary Newport's husband, shows remarkable responses (stopping tremors, improving cognition even in APOE4 positive individuals), clinical trials are needed. Ketogenic diets alter brain metabolism and pharmacology, making them an important area of study for these conditions.

How might ketones help with migraines and inflammation?

Ketogenic diets and ketone supplements have shown anecdotal efficacy in managing chronic migraines, possibly through multimodal mechanisms. These include increased GABAergic tone, altered brain blood flow (potentially via adenosine-induced vasodilation), and reductions in neuroinflammation. Ketones can also mitigate inflammatory cascades associated with viral episodes like shingles or herpes simplex, which often begin with crushing headaches.

How can ketogenic diets be applied as an adjuvant therapy for cancer?

Ketogenic diets, especially when calorie-restricted, put metabolic stress on cancer cells, limit glucose availability, and suppress insulin signaling. This makes tumors more sensitive to chemotherapy and radiation, causing more tumor cell death while protecting healthy cells. They also augment the immune system to recognize and attack cancer cells more effectively. Certain aggressive and glycolytic cancers, like gliomas, tend to be more responsive.

What are the best methods for measuring ketone levels?

For initial assessment, urine strips can confirm ketosis. For quantitative and sustained monitoring, a blood ketone meter (like Keto-Mojo) is good. For tracking fat oxidation and long-term weight loss goals, a breath acetone meter (like Biosense) is recommended as acetone directly reflects fat metabolism and is more stable than blood BHB levels during activity. Continuous Glucose Monitors (CGMs) can also infer ketogenic adherence by showing a flat glucose trace.

Key Moments

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

FoundMyFitness

Science & Technology6 min read164 min video

Apr 28, 2022|144,965 views|2,736|253

ketogenic diet keto diet dominic dagostino dr. dominic dagostino dominic dagostino cancer dom dagostino fasting dom dagostino exogenous ketones dom dagostino diet dom dagostino ketogenic diet dr dominic dagostino exogenous ketones cancer autoimmune disease

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TL;DR

Dr. Dom D'Agostino discusses ketogenic diets, focusing on science, variations, and exogenous ketones.

Key Insights

Ketogenic diets are defined by objective biomarker (ketones) measurable in blood, urine, or breath.

Variations of ketogenic diets exist, from classical (high fat) to modified (lower fat, more liberal protein/carbs), each with therapeutic effects.

Exogenous ketones offer benefits, especially for those unable or unwilling to follow a strict ketogenic diet.

Combining a modified ketogenic diet with exogenous ketone supplementation may offer an optimized lifestyle approach.

Ketones play a role in preserving muscle mass, promoting metabolic health, and potentially enhancing brain function.

While promising, research is ongoing for ketogenic diets and supplements in areas like neurodegenerative disorders, cancer, and autoimmune diseases.

THE SCIENCE AND VARIATIONS OF KETOGENIC DIETS

Dr. Dominic D'Agostino clarifies that a ketogenic diet is scientifically defined by the presence of ketones, measurable in blood, urine, or breath. He distinguishes between the classical ketogenic diet, which is very high in fat and used for conditions like epilepsy, and more liberal variations such as Modified Atkins or Low Glycemic Index Therapy. These variations, while still carbohydrate-restricted, allow for more protein and fat, potentially making them more suitable for lifestyle application and offering therapeutic benefits independent of very high ketone levels.

IMPLEMENTING KETOGENIC DIETS SAFELY

Initiating a ketogenic diet requires careful consideration, especially for therapeutic purposes. D'Agostino suggests a gradual transition over several weeks, particularly for those not accustomed to carbohydrate restriction, to mitigate side effects like sleep disruption or lipid abnormalities that can occur with abrupt changes. For lifestyle changes, he emphasizes incorporating fiber, healthy fats, and phytonutrients, noting that fiber is crucial for gut health and can moderate digestion and nutrient absorption, contributing to overall well-being.

EXOGENOUS KETONES: A SUPPLEMENTAL APPROACH

Exogenous ketones, available as esters or salts, can raise ketone levels without requiring strict dietary adherence. D'Agostino explains that these supplements can mimic some benefits of the ketogenic diet, serving as an alternative energy source for the brain and potentially offering benefits for individuals unable or unwilling to maintain a ketogenic diet. He highlights that different formulations have varying pharmacokinetic profiles and potential side effects, and their combination with MCTs can lead to sustained ketosis.

KETONES AND METABOLIC HEALTH

Ketones offer a unique metabolic advantage, acting as an alternative fuel source and signaling molecules. D'Agostino discusses their potential role in preserving muscle mass, especially during calorie restriction, by providing the brain with energy and preventing the breakdown of muscle tissue for glucose. He also touches upon anti-inflammatory effects and potential benefits for cognitive function and neurological disorders, emphasizing that ketones can reduce reliance on glucose and mitigate energy crises in the brain.

APPLICATIONS IN NEUROLOGICAL AND METABOLIC DISORDERS

The ketogenic diet remains a well-established therapy for epilepsy and certain metabolic disorders. D'Agostino also explores its potential in neurodegenerative diseases like Alzheimer's and Parkinson's, noting anecdotal evidence and ongoing research that suggest benefits in cognitive function and symptom management. He emphasizes the importance of personalized approaches, as responses can vary significantly between individuals.

KETOGENIC DIETS, EXERCISE, AND CANCER THERAPY

Regarding exercise, ketones may offer a small benefit for aerobic performance and act as a potent ergogenic aid in extreme environments like hypoxia. D'Agostino also discusses the synergistic potential of ketogenic diets with conventional cancer therapies. By creating metabolic stress on cancer cells and enhancing the immune system, ketogenic diets may improve treatment efficacy and protect healthy cells, although research is still in early stages for many applications.

THE ROLE OF KETONES IN MUSCLE MASS PRESERVATION

Ketones play a significant role in preventing muscle loss, particularly during periods of fasting or calorie restriction. D'Agostino explains that as the body turns to fat for fuel, ketones provide essential energy to the brain, sparing muscle tissue. This anti-catabolic effect is crucial for maintaining muscle mass, which is vital for healthy aging and recovery, and can be further supported by the anti-inflammatory properties of ketones.

MYTHS, MISCONCEPTIONS, AND MONITORING KETOSIS

D'Agostino addresses common misconceptions, such as the idea that calories don't matter on a ketogenic diet. He stresses the importance of monitoring various biomarkers, including glucose, ketones (via blood, breath, or urine), and lipid profiles, to assess individual responses. He also notes that many commercially available 'keto-friendly' products can still negatively impact blood glucose and ketone levels, highlighting the need for careful label reading and adherence to a well-formulated diet.

RESEARCH ON EXOGENOUS KETONE FORMULATIONS

The development of exogenous ketone supplements, including esters and salts, is a rapidly advancing field. D'Agostino differentiates between these forms, explaining how ketone esters can lead to a rapid increase in blood ketones, sometimes causing a counter-regulatory insulin response. Ketone salts, especially when combined with MCTs, tend to offer a more sustained and moderate rise in ketones, which may be more physiologically advantageous for certain applications and reduce potential side effects.

INSIGHTS ON VITAMIN D AND ADAPTOGENIC THERAPIES

The discussion touches on the importance of Vitamin D supplementation and individual responses, suggesting that genetic factors and supplement quality can influence efficacy. D'Agostino also briefly mentions 'hot tub therapy' or hyperthermia, noting personal observations of decreased blood pressure and improved markers, hinting at broader applications of environmental therapies for health optimization beyond diet alone.

THE POTENTIAL OF KETONE THERAPY FOR VARIOUS DISORDERS

Beyond epilepsy, D'Agostino highlights promising research for ketogenic diets and exogenous ketones in managing migraines, inflammation-associated conditions like herpes simplex and shingles, and autoimmune disorders. He proposes that these interventions work through multiple mechanisms, including modulating neurotransmitter systems, improving blood flow, reducing inflammation, and influencing the gut microbiome, suggesting a broad therapeutic potential for brain and immune health.

UNDERSTANDING THE WARBURG EFFECT AND CANCER

D'Agostino elaborates on the Warburg effect, where cancer cells exhibit altered metabolism, often relying heavily on glucose. He explains how ketogenic diets and ketones can specifically target and stress these cancer cells by limiting glucose availability and potentially hindering their growth, especially in aggressive or glycolytic cancers. This metabolic targeting makes the ketogenic diet a promising adjuvant therapy alongside conventional cancer treatments.

THE CARNIVORE DIET: THERAPEUTIC OR SUB-OPTIMAL?

While acknowledging that the carnivore diet has benefited some individuals, D'Agostino expresses caution regarding its long-term optimality. He notes that while it can be ketogenic, it may lead to concerning changes in biomarkers like LDL cholesterol and triglycerides. He suggests that benefits might stem from calorie restriction or eliminating processed foods, but the lack of fiber and phytonutrients makes it potentially sub-optimal compared to a more diverse, well-formulated ketogenic diet.

MEASURING KETONES AND GLUCOSE MONITORING

D'Agostino explains the different methods for measuring ketones: urine strips (semi-quantitative, good for initial assessment), blood meters (accurate, quantitative), and breath analyzers (good for fat oxidation). He emphasizes the value of continuous glucose monitoring (CGM) as an indirect indicator of adherence to a ketogenic diet, noting that a stable, low glucose trace usually correlates with ketosis. CGM offers insights into how food choices and lifestyle impact metabolic health.

Mentioned in This Episode

●Supplements

●Products

●Software & Apps

●Tools

●Companies

●Organizations

●Concepts

●People Referenced

Optimizing Ketogenic Diet & Ketone Supplementation

Practical takeaways from this episode

Do This

Gradually titrate carbohydrates down over 4-6 weeks when starting a ketogenic diet for lifestyle.

Incorporate lots of fiber (non-glycemic fibrous vegetables, raw leafy greens) to support gut microbiome and moderate digestion.

Choose monounsaturated fats (avocados, nuts, olive oil) and omega-3 fatty acids (salmon) in your diet.

Consider ketone supplements (ketone salts, MCT oil) for sustained ketone elevation and anti-catabolic effects.

Take ketone supplements with electrolytes (sodium, potassium, calcium, magnesium) to prevent depletion.

Supplement with Creatine, Acetyl-L-Carnitine, Taurine, Omega-3s, and Magnesium.

Monitor blood glucose and ketones (using a CGM, blood ketone meter, or breath acetone meter) to observe dietary adherence and metabolic response.

Periodize training in a semi-fasted (low glucose, low insulin) state to induce metabolic adaptations and flexibility.

Experiment methodically with new dietary or supplement approaches well before a competitive event.

Consider cyclical ketosis or intermittent fasting for optimal benefits and sustainability.

Avoid This

Abruptly start a ketogenic diet, as it can lead to side effects like sleep disruption, lipid abnormalities, and triglyceride spikes.

Consume extremely high saturated fats, especially if you have the APOE4 allele.

Take large, rapid-spiking doses of ketone esters on an empty stomach, as it can cause an insulin release and potentially metabolic acidosis if ketones exceed 3 millimolar.

Rely on urine ketone strips for accurate quantitative measurement; choose blood or breath meters for precision.

Assume all 'keto' labeled products are genuinely ketogenic; always check ingredients for hidden sugars.

Ignore calorie intake on a ketogenic diet, as caloric density is high and can lead to overconsumption.

Exclusively follow a carnivore diet long-term, as it may be sub-optimal due to lack of fiber and phytonutrients for most individuals.

Common Questions

Ketogenesis is the process of producing ketones, which are objective biomarkers defining a ketogenic diet. This diet suppresses insulin, depletes liver glycogen, and accelerates fatty acid oxidation, leading to the production of acetoacetate and beta-hydroxybutyrate. A classical ketogenic diet can be 80-90% fat with very low carbohydrates and moderate protein, while modified versions like a 1:1 ratio are less restrictive.

Topics

Ketone Supplements Neurodegenerative Disease Blood Glucose Monitoring

Mentioned in this video

Concepts

Carnitine Palmitoyltransferase I (CPT1) Deficiency

An inborn error of metabolism that is contraindicated with a ketogenic diet, as it can be deadly due to impaired fat metabolism.

PDL-1 Inhibitors

Checkpoint inhibitors used in cancer immunotherapy, whose efficacy was greatly augmented in the context of a ketogenic diet according to recent research.

Pyruvate Dehydrogenase (PDH) Deficiency

A metabolic disorder where the ketogenic diet can be therapeutically beneficial.

C57 Black 6 Mice

A strain of mice that can eat a lot of ketogenic diet without gaining weight, often considered 'athlete mice'.

VMDK Mice

A strain of mice used in cancer research where a ketogenic diet corrects eating behavior and leads to weight loss and improved health, resembling 'sedentary mice'.

condition

Kabuki Syndrome

A rare genetic disease with neurological abnormalities and seizures, where the ketogenic diet has been shown to be therapeutic by silencing these abnormalities.

Glucose Transporter Type 1 Deficiency Syndrome (GLUT1-DS)

A metabolic disorder where the ketogenic diet is a widely accepted application due to impaired glucose transport to the brain, benefiting from ketones as an alternative energy source.

Angelman Syndrome

A neurological disorder known to be seizure-responsive to the ketogenic diet; animal models showed improved learning and memory with ketone ester administration.

People

Lou Cantley

Researcher spearheading work on PI3-kinase inhibitors and their enhanced efficacy with ketogenic diets.

John Freeman

Late researcher from Johns Hopkins, pioneering in ketogenic diet research, who collaborated with Dr. Eric Kossoff on modified Atkins diet for adult epilepsy.

Eric Verdin

A mutual friend and researcher whose preclinical mouse studies showed improved health span, median lifespan, and cognition with a cyclical ketogenic diet.

Mark Mattson

Long-time researcher in fasting and ketogenic diets, whose work inspired Dr. D'Agostino and showed benefits of intermittent fasting linked to beta-hydroxybutyrate induced growth factor effects.

Theodore Van Itallie

A friend and collaborator in ketone research, acknowledged for his contributions to the field.

John Ramsey

Co-published studies with Dr. Eric Verdin showing benefits of cyclical and time-restricted ketogenic diets in mice for health span and cognition.

Adrian Scheck

A colleague who researched glioblastoma cell lines, demonstrating enhanced cancer-specific immune regulation with dietary intervention, radiation, and ketogenic diets.

Shawn Baker

A prominent advocate of the carnivore diet, described as a 'physical specimen' who appears to thrive on an all-meat diet.

Mary Newport

One of the key inspirations for Dr. D'Agostino, who observed her husband's remarkable response to coconut oil and later ketone esters for Alzheimer's and Parkinson's-like symptoms, despite being APOE4 positive.

Angela Poff

A PhD student of Dr. D'Agostino who replicated his in vitro cancer research in animal models, showing synergistic effects of ketogenic diet and hyperbaric oxygen, and later ketone supplementation.

Hans Bejornsen

Researcher at Johns Hopkins whose lab demonstrated that the ketogenic diet silenced neurological abnormalities in Kabuki Syndrome.

Elena Gross

A PhD student (now Doctor) who co-authored a review on migraines and discovered how ketogenic diets and ketone supplements helped manage her chronic migraines.

Mackenzie Cervanka

Part of the Johns Hopkins team advocating for various types of ketogenic diets and patient-specific adjustments.

Richard Veech

A pioneer in the field of ketone research, acknowledged for developing the rationale and testing of ketone esters.

Products

Walgreen's/CVS Vitamin D Supplement

Generic Vitamin D supplements that Dr. D'Agostino found ineffective in raising his Vitamin D levels despite high dosing, likely due to inconsistent concentration.

Readout Health Biosense Device

An FDA-approved class one medical device for measuring breath acetone, which is a reliable indicator of fat oxidation and correlates with seizure control, offering a cost-effective alternative to blood ketone meters for monitoring.

Bio-Optimizers Magnesium Breakthrough

A magnesium supplement with five or six different forms of magnesium, mentioned by Dr. D'Agostino for effectively elevating blood magnesium levels.

Keto Brainz Coffee Creamer

A coffee creamer that Dr. D'Agostino uses daily, containing Alpha GPC, L-Theanine, Lion's Mane, and C8 MCT, designed to enhance focus and provide ketogenic fats.

AC1202 (Caprylic Triglyceride)

A product by Xera (now Accera) designed for Alzheimer's disease, showing improvements in mild cognitive impairment associated with ketones, though not in ApoE4 carriers in initial studies.

Keto-Mojo Device

A blood ketone meter recommended for individuals starting a ketogenic diet, providing more accurate quantitative ketone measurements than urine strips.

Mind Body Green Vitamin D Supplement

A Vitamin D supplement that successfully maintained elevated Vitamin D levels for Dr. D'Agostino, unlike previous brands.

Abbott Lingo Device

A continuous monitoring system (currently in development) that tracks glucose, ketones, lactate, and alcohol, indicating the future of metabolic monitoring.

Thorne Vitamin D3 from Lichen

A Vitamin D3 supplement derived from lichen, suitable for vegetarians.

Keto Brick

A high-fat, high-calorie, low-carbohydrate bar (1000 calories, 90g fat, 30g protein) described as the 'only truly ketogenic bar' by Dr. D'Agostino, due to its macronutrient profile and lack of hidden sugars.

Software & Apps

Levels Health App

A continuous glucose monitoring (CGM) app that provides coaching, nutritional insights, and daily/weekly metabolic reports, helping users understand their glycemic response to food and activities.

Zero Fasting App

A fasting tracker app that is collaborating with Readout Health Biosense device, mentioned as a companion for fasting protocols.

ClinicalTrials.gov

Organizations

Labdoor

A third-party site that tests the concentration of active ingredients in supplements, recommended for checking Vitamin D3 levels.

Institute for Human and Machine Cognition (IHMC)

Research institute where Dr. D'Agostino is a research scientist, focusing on various research areas including metabolic therapies.

ConsumerLab.com

A third-party site that tests the concentration of active ingredients in supplements, recommended for checking Vitamin D3 levels.

Moffitt Cancer Center

A cancer center interested in immune-based therapies, including the use of ketogenic diets to enhance checkpoint inhibitors like PDL-1 inhibitors.

Supplements

2-Deoxyglucose (2-DG)

A glycolytic inhibitor with strong anti-seizure effects, currently advocated and used clinically in some studies as a 'ketogenic diet in a drug,' but has cardiotoxic effects at higher doses.

PI3-Kinase Inhibitors

Metabolic drugs that target tumor metabolism and are remarkably effective, but have a counter-regulatory effect of increasing insulin. Their efficacy is greatly enhanced when combined with a ketogenic diet to suppress insulin.

KetoStart

An exogenous ketone product (ketone salt) that Dr. D'Agostino uses daily, recommending half a packet at a time to avoid insulin spikes.

Cytomax (Alpha-L Polylactate)

A lactate-based energy supplement used by Dr. D'Agostino for mountain biking, highlighting lactate's under-appreciated role as a brain fuel.

C8 MCT

Caprylic acid, a type of medium-chain triglyceride, included in Keto Brainz coffee creamer for rapid ketone production.

Companies

Xera

Company that produced AC1202, a caprylic triglyceride product researched for Alzheimer's disease.