How can I start ketosis without supplements?

You can jumpstart ketosis without supplements primarily through exercise. A moderate walk, potentially preceded by brief high-intensity intervals, can help activate the sympathetic nervous system and mobilize fatty acids for fuel, supporting the transition into ketosis.

How do I maintain lean muscle mass while fasting?

While fasting can lead to water weight loss, mitigating muscle loss can involve consuming Branch Chain Amino Acids (BCAAs). Additionally, a physiological shift during fasting into ketosis provides a protein-sparing effect, as the brain utilizes ketones instead of breaking down muscle.

What is the glucose-ketone index and why is it important?

The glucose-ketone index is a ratio of blood glucose to blood ketones, aiming for a value of one or two. Achieving this 'metabolic zone,' as described by Tom Seyfried, is thought to be physiologically optimized and potentially therapeutic for conditions like cancer.

How long does it take to become fat-adapted on a ketogenic diet for endurance athletes?

Becoming fully fat-adapted on a ketogenic diet can take a significant amount of time, ranging from months to potentially years. Advanced athletes have reported taking as long as six months to feel truly optimized and find their stride with the diet.

Should ApoE4 carriers be cautious with the ketogenic diet?

While MCT oil supplementation showed less favorable results in ApoE4 positive individuals in one study, carbohydrate restriction associated with nutritional ketosis may be beneficial. Ketosis and fasting can activate pathways downregulated by the ApoE4 genotype and attenuate pro-inflammatory pathways.

Are there downsides to occasional cheat meals when following a ketogenic diet?

For performance purposes, occasional 'refeeds' or cheat meals generally pose no downside unless managing a disease process. However, they can lead to nighttime hunger due to insulin response and potential hypoglycemia. A slow-carb approach with sufficient fats might yield better results.

Do ketogenic diets offer a metabolic advantage?

The claim of 'no metabolic advantage' often arises in isocaloric studies. However, proponents argue the primary advantage lies in appetite suppression, leading to a natural reduction in calorie intake and reduced blood glucose fluctuations, thus mitigating cravings.

What are Dom D'Agostino's primary fat sources on a ketogenic diet?

Dom D'Agostino's primary fat sources include eggs, avocados, olive oil, MCT oil (or coconut oil), fatty meats, and fatty fish. He also consumes macadamia nuts in moderation and avoids dairy due to intolerance.

Is Metformin beneficial for longevity?

Metformin is being studied for its potential longevity effects, showing promise as a calorie restriction mimetic by lowering glucose and insulin, and potentially elevating ketones. However, research is ongoing, and long-term studies are needed. Potential side effects and interactions should be considered.

Can the ketogenic diet be used for glycolytic training like Muay Thai?

Yes, the ketogenic diet can be adapted for glycolytic training, but it requires consistent adaptation over several months. Supplementing with creatine and consuming red meat can help maintain power and strength, alongside sufficient fat adaptation.

What are the health consequences of carb backloading and large glucose spikes?

Routinely exceeding glucose levels of 140 mg/dL can lead to irreversible beta cell loss, nerve damage, and increased cancer risk. Stroke risk also correlates with postmeal blood sugar rises. A slow-carb approach to backloading is recommended to mitigate these risks.

Are DL-beta-hydroxybutyrate ketone salts safe?

Despite concerns raised about racemic compounds, evidence suggests DL-beta-hydroxybutyrate salts have been consumed safely in millions of doses worldwide with few reported adverse effects beyond potential gastrointestinal issues at high doses. They have shown benefits in suppressing seizures and inflammation.

Key Moments

Dom D'Agostino Returns (Full Episode) | The Tim Ferriss Show (Podcast)

Tim Ferriss

Howto & Style5 min read84 min video

Oct 20, 2016|12,006 views|127|5

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Key Moments

TL;DR

Dom D'Agostino discusses ketones, cancer, fasting, and longevity with Tim Ferriss.

Key Insights

The ketogenic diet can be a valuable adjunct therapy for certain aggressive cancers, especially when conventional treatments are less effective.

Nutritional ketosis may enhance the efficacy of radiation therapy for brain tumors by reducing tumor cell's glycolytic flux and protecting healthy tissue.

Fasting can stimulate autophagy and immune surveillance, but prolonged fasting or calorie restriction can suppress the immune system; lean muscle mass can be preserved with BCAAs.

While ketogenic diets may not always show a direct metabolic advantage over isocaloric diets in short-term studies, they offer significant benefits in appetite suppression and reduced cravings.

Longevity and health are linked to strength training, mitochondrial health (enhanced by ketosis and fasting), and potentially HIIT, but extreme bodybuilding regimens can be detrimental.

Carb backloading can be effective for muscle gain and glycogen restoration, but careful titration of carbohydrates is crucial to avoid negative health consequences like beta-cell damage.

KETOGENIC DIETS AS ADJUNCT CANCER THERAPY

Dr. Dom D'Agostino clarifies that the ketogenic diet is not a universal cure for all cancers but can be a powerful supportive therapy. He highlights its potential for aggressive and treatment-resistant cancers, such as glioblastomas, which exhibit the Warburg effect (high glycolytic rate). The diet, when properly administered, can synergistically enhance the efficacy of standard treatments like chemotherapy and radiation, potentially reducing side effects and improving patient outcomes. This metabolic-based approach targets the altered metabolism of cancer cells.

ENHANCING RADIATION THERAPY WITH KETOSIS

Research, particularly the work of Dr. Adrienne Scheck, suggests that nutritional ketosis significantly boosts the effectiveness of radiation therapy for brain tumors. By limiting the tumor's reliance on glucose (glycolytic flux), ketosis may impair the cancer cells' antioxidant mechanisms, such as the pentose phosphate pathway, making them more vulnerable to radiation-induced oxidative stress. Simultaneously, ketones can reduce inflammation in healthy brain tissue, offering a protective effect.

FASTING, AUTOPHAGY, AND MUSCLE PRESERVATION

Fasting can induce autophagy, a cellular cleaning process that may enhance immune function against pre-cancerous cells. However, extended fasting or severe calorie restriction can compromise the immune system. To mitigate muscle loss during fasting, branched-chain amino acids (BCAAs) are recommended, especially if any exercise is performed. The body's physiological shift into fasting ketosis also offers a protein-sparing effect by preventing muscle breakdown for glucose.

METABOLIC ZONE AND CANCER TARGETING

The 'metabolic zone,' defined by a glucose-ketone index of around 1 (equal levels of glucose and ketones), is considered an optimal therapeutic state for managing cancer. This state is achievable through ketogenic diets, ketone supplements, and intermittent fasting. This approach is particularly effective for the 80-90% of cancers that exhibit the Warburg phenotype (high glycolytic rate), as identified by PET scans, which indicate rapid glucose consumption for tumor biomass.

KETOSIS AND LONGEVITY STRATEGIES

For longevity, the focus shifts from maximum size and strength (which often requires calorie surplus) to maintaining muscle mass through strength training and optimizing mitochondrial health via nutritional ketosis and intermittent fasting. While intense resistance training is crucial, the pursuit of extreme bodybuilding can be counterproductive to longevity. High-intensity interval training (HIIT) is also suggested as beneficial, though difficult for some to incorporate consistently.

CARB BACKLOADING AND SAFETY CONSIDERATIONS

Carb backloading, consuming carbohydrates after a workout, can aid in size and strength gains by optimizing glycogen restoration. However, careful management is needed to prevent excessive postprandial glucose spikes, which can lead to beta-cell damage, nerve damage, and increased cancer risk. A slow-carb approach with lower glycemic options and controlled portions is advised. Safety concerns regarding racemic DL beta-hydroxybutyrate salts in ketone supplements are discussed, with the consensus being that extensive real-world use and existing studies suggest their safety when consumed appropriately.

APOE4 CARRIERS AND DIETARY STRATEGIES

Individuals with the APOE4 gene may benefit from ketogenic diets, intermittent fasting, and calorie restriction due to their ability to attenuate pro-inflammatory pathways. While MCT oil supplementation showed limited cognitive benefits in one study, carbohydrate restriction associated with nutritional ketosis appears more favorable. These metabolic interventions can help mitigate the heightened inflammatory effects associated with the APOE4 genotype, especially as people age. Supplements like berberine and potentially metformin are also considered.

METFORMIN AND LONGEVITY RESEARCH

Metformin, a diabetes drug, is being investigated for its potential longevity benefits, acting as a calorie restriction mimetic. While it can lower blood glucose and insulin, and potentially increase ketones, its effect on lifespan in human studies is still under investigation. Long-term concerns include potential GI discomfort, vitamin B12 absorption issues, and a possible photosensitivity reaction. Its role in longevity remains a subject of ongoing research, with ongoing trials looking into its impact on aging biology.

TRAINING ADAPTATIONS ON A KETOGENIC DIET

For athletes, particularly in glycolytic sports like Muay Thai, adapting to a ketogenic diet typically requires three to six months of consistent adherence. Supplementing with creatine and ensuring adequate red meat intake can help maintain power and strength. While short-term studies may show performance decreases due to insufficient keto-adaptation, long-term adaptation leads to significantly improved fat oxidation, preserving glycogen stores for endurance and high-intensity efforts. Creatine monohydrate is recommended for those on ketogenic diets for glycolytic training.

ACADEMIA AND ATHLETIC PURSUITS

Dr. D'Agostino's journey highlights how rigorous athletic training, particularly weightlifting, instilled discipline, structure, and resilience, complementing his academic career. The planning, self-evaluation, and dedication required for serious training translated into his scientific pursuits. While intense bodybuilding can contradict longevity goals due to necessary calorie surplus, maintaining strength through moderate training remains a priority, emphasizing flexibility and creativity in fitting workouts into a demanding schedule, even during travel.

Mentioned in This Episode

●Supplements

●Products

●Software & Apps

●Companies

●Organizations

●Books

●Drugs & Medications

●People Referenced

Ketogenic Diet and Lifestyle Guide

Practical takeaways from this episode

Do This

Consider the ketogenic diet as an adjuvant or support for various cancer therapies, especially aggressive and metastatic cancers like glioblastoma.

Properly administered ketogenic diets can enhance the efficacy of standard cancer care and potentially reduce side effects.

Pairing the ketogenic diet with intermittent fasting or hyperbaric oxygen therapy may further augment therapeutic efficacy.

Aim for a glucose-ketone index of one, as described by Tom Seyfried, for an potentially optimal therapeutic zone.

Jumpstart ketosis through exercise like a moderate walk, possibly preceded by short high-intensity intervals.

Mitigate lean muscle loss during fasting with Branch Chain Amino Acids (BCAAs) and consider 5-HTP for hunger cravings and sleep.

For ApoE4 carriers, prioritize carbohydrate restriction and nutritional ketosis, alongside intermittent fasting, exercise, and strength training.

For performance, occasional cheat meals are generally fine, but consider a slow-carb approach with sufficient fats.

If doing carb backloading, aim for 100-200 grams of carbohydrates post-workout, focusing on lower glycemic options and slow consumption.

Prioritize strength training at least twice a week for longevity to preserve skeletal muscle mass.

Combine nutritional ketosis and intermittent fasting to enhance mitochondrial health and vitality.

If on a ketogenic diet and engaging in glycolytic training, consider supplementing with creatine.

For academic and scientific pursuits, maintain rigorous planning, note-taking, self-evaluation, and discipline.

Avoid This

Do not consider the ketogenic diet as a replacement for chemotherapy for all cancers; it is primarily an adjuvant.

Avoid vigorous exercise when jumpstarting ketosis; opt for lower-impact activities.

Do not fast or calorie restrict for excessively long periods, as this can suppress the immune system.

Avoid eating excessively high amounts of carbohydrates in a single sitting, as this can lead to negative health consequences like beta cell loss and increased cancer/stroke risk.

Be cautious with extremely high doses of ketone salts, which can lead to diarrhea or loose stools.

Do not solely rely on ketone salts for therapeutic purposes without clinical trials.

Avoid pursuing extreme size and strength in weight training if longevity is the primary goal, as this often requires a caloric surplus.

Do not expect immediate performance benefits from a ketogenic diet; adaptation can take months to years.

Common Questions

No, the ketogenic diet should not be seen as a replacement for chemotherapy for all cancers. However, it can be a valuable adjuvant or support therapy, particularly for aggressive and metastatic cancers like glioblastoma, potentially enhancing the efficacy of standard treatments.

Topics

Ketogenic Diet Intermittent Fasting Longevity Metabolic Health Health & Longevity Neuroscience & the Brain Nutrition & Diet Athletic Performance Cancer Therapy

Mentioned in this video

Organizations

Department of Defense

A government department supporting Dominic D'Agostino's research.

University of Alabama

Conducting a multi-year trial on Metformin and longevity.

University of South Florida Morsani College of Medicine

The institution where Dominic D'Agostino serves as an associate professor in the department of molecular pharmacology and physiology.

Institute for Human and Machine Cognition

A research institute where Dominic D'Agostino is a senior research scientist, known for its work on human and machine cognition.

Office of Naval Research

An organization supporting Dominic D'Agostino's research on metabolic therapies for performance and resilience in extreme environments.

Barrow Neurological Institute

An institute where Dr. Adrian Shiels conducts research on glioblastoma, and where Dr. Jung GR previously worked.

Books

Nutrition & Metabolism

A journal where Tom Seyfried published a paper on the glucose-ketone index.

People

Johnny Valer

Asked whether ApoE4 carriers should be cautious with the ketogenic diet.

Daniel Barrena

Asked for thoughts on John Kiefer's carb night protocol or carb backloading.

George Cahill

His work at Harvard is cited for demonstrating the protein-sparing effect of fasting and ketosis.

Dominic D'Agostino

An associate professor and senior research scientist focusing on metabolic therapies, ketogenic diets, and their application in peak performance, resilience, and disease prevention, particularly cancer.

Peter Attia

A guest on the Tim Ferriss Show, mentioned as a friend of Dominic D'Agostino.

Adrian Shiels

A researcher at Barrow Neurological Institute whose work on preclinical mouse models of glioblastoma inspired a clinical trial combining the ketogenic diet with standard care (Temozolomide and radiation).

Jung GR

A leading ketogenic diet researcher and current chair of Pediatrics in Calgary, who previously directed D'Agostino to Adrian Shiels' work.

Tom Seyfried

Mentioned for his work on the 'metabolic zone' and the glucose-ketone index, which he describes in a paper in Nutrition & Metabolism.

Ramsey Metf

An individual who asked questions about the detoxifying effects of ketosis on precancerous cells, jumpstarting ketosis without supplements, and maintaining lean muscle mass during fasting.

Ronda Patrick

Mentioned in relation to Dominic D'Agostino's participation in a podcast and specific questions received by D'Agostino.

Leen Norton

Mentioned for his PhD work on leucine and its anabolic/anti-catabolic effects, conducted in Donald Layman's lab.

Upton Sinclair

Author of 'The Fasting Cure', a book available as a free PDF download.

Lowell Kubic

Asked about updates on ketosis and chemotherapy recovery, and the types of cancers ketosis impacts most.

Brent Reynolds

Conducting preclinical work on colon cancer, breast cancer, and glioblastoma at the University of Florida, using patient-derived xenograph models.

Melanie Schmidt

Author of a pilot trial paper on the effects of the ketogenic diet on the quality of life in patients with advanced cancer.

Scott Shear

Asked about the interplay between ketosis and hyperbaric oxygen therapy.

Justin Bowman

Asked about the duration of ketosis needed for fat adaptation in amateur endurance athletes and recommended supplement stacks for marathons.

Ben Greenfield

Mentioned for his extensive discussions on intra-race supplementation.

Sam Henderson

Conducted a study on an MCT oil-based product (AC202) in patients with mild cognitive impairment, finding that ApoE4 positive individuals did not respond as favorably.

Dale Bredesen

Guest on IHMC Stem Talk (episode 12) discussing ApoE4 and actionable strategies to mitigate its effects.

Matthew Maveri

Asked about the downsides of occasional cheat meals in relation to ketosis.

Angela Poff

Research associate who was first author on several manuscripts discussing the combination of ketogenic diet and hyperbaric oxygen therapy.

Arnold Schwarzenegger

Author of 'The Education of a Bodybuilder', a book that influenced D'Agostino's mindset towards discipline and hard work from a young age.

Bruce Grabber

Developed an ester at Case Western that elevated both beta-hydroxybutyrate and acetoacetate, used in CNS oxygen toxicity seizure studies.

Andrew Scarborough

Featured on Quantified Body podcast, discussing his management of a Grade Three brain tumor using the ketogenic diet and supplements.

David Ludwig

Mentioned for a 10-minute YouTube video offering a counterargument to the claim that ketogenic diets have no metabolic advantage.

Jeff Volek

Conducted the 'Faster' study, which observed athletes adapted to a ketogenic diet for over a year burning significantly more fat during training.

Hamilton R. Blair

Asked about Dominic D'Agostino's primary fat sources on a modified ketogenic diet, given sensitivities to dairy and nuts.

Dave Asprey

Co-hosted a podcast with Ben Greenfield where Dr. Beach discussed potential dangers of DL-beta-hydroxybutyrate salts.

Damian Matthews

Asked for thoughts on non-food substances like Metformin or Methylene Blue for longevity.

Josh Bracket

Asked whether the ketogenic diet can be used for glycolytic training, specifically in Muay Thai.

Gerard E. Dawson II

Asked about the experience of being an academic who also prioritizes serious weight training, and how these pursuits complement or complicate each other.

John Kiefer

Associated with the 'carb night' or 'carb backloading' strategy for gaining size and strength.

Tim Ferriss

Host of the podcast, introducing guests, sponsors, and sharing personal insights and recommendations.

Drugs & Medications

Ephedrine

Mentioned as an example of a racemic drug that is proven safe.

Ibuprofen

Mentioned as an example of a racemic drug that is proven safe.

Pseudoephedrine

Mentioned as an example of a racemic drug that is proven safe.

Metformin

A drug being studied for its potential effects on aging, gene expression, and longevity, with ongoing trials like the MILE study. It may mimic calorie restriction effects and elevate ketones.

Software & Apps

Vimeo

A platform offering business solutions for video creation, sharing, and marketing, including features for collaboration, storage, and analytics.

Four Hour Work Week

Mentioned as the URL to sign up for Tim Ferriss's Five Bullet Friday email newsletter.

Companies

Wealthfront

An investing service that uses software to offer services previously reserved for the ultra-wealthy, focusing on automation, low costs, and features like tax-loss harvesting and rebalancing.

Ketopia

Manufacturer of ketone products containing DL-beta-hydroxybutyrate salts.

Keto Forever Green

Manufacturer of ketone products containing DL-beta-hydroxybutyrate salts.

KetoSports

Manufacturer of ketone products containing DL-beta-hydroxybutyrate salts.

Kenix

Manufacturer of ketone products which contain DL-beta-hydroxybutyrate salts.

Supplements

5-HTP

A serotonin precursor that may help reduce hunger cravings at night and aid sleep, especially when fasting.

Methylene blue