July 25, 2020

It's time for a serious geek out on all things ketones, ketosis, ketone esters, and more!

My guest on today's show, Geoffrey Woo, is co-founder and CEO of H.V.M.N. – Health Via Modern Nutrition. He is also the host of the Health Via Modern Nutrition Podcast, a health & performance podcast that recently broke 4 million downloads. H.V.M.N. helped popularize ketones as a food group beyond fats, proteins, and carbohydrates and makes foods & supplements for metabolic performance and health—fueling some of the world's top performers, athletes, and military service members.

Geoff is an avid self-experimenter who like to do 7-day water fasts, has inspired thousands under the COVID-19 lockdown to push themselves with positive challenges by completing the Crossfit Murph workout for 45 days in a row, and studies the optimization of human performance—at the individual scale, the team scale, the organization scale, and at the civilizational scale. He holds a BS with honors and distinction in computer science from Stanford University.

During this discussion, you'll discover:

-How Geoffrey used ketone esters while doing a Crossfit “Murph” for 45 consecutive days…5:45

• Named after Michael Murphy, a Navy SEAL killed in Afghanistan
• Consists of a 1-mile run, 100 pullups, 200 pushups, 300 squats, then another mile run
• Staying with a routine when COVID-19 became a serious issue
• Low carb diet overall
• Need for muscle and liver glycogen repletion
• Added carbs to the diet, as well as ketone esters and exogenous ketones
• Used ketones more for recovery than for performance

-Why ketogenesis is not a physiologically typical state…13:00

• It's a “backup” metabolic process in a carb-restricted state
• Ketones a “fourth macronutrient”
• Ketosis is not an endpoint, but a starting point into metabolism

-The role ketones play when it comes to recovery…16:15

• Research thus far has been focused on acute performance benefits
• Trials performed on runners and cyclists; much easier to quantify than other sports
• Tour de France cyclists reported exogenous ketones were better for recovery than for pre-race fuel
• 2019 study on mimicking Tour de France training regimen with ketone esters
• Ketones plus carbs and protein upregulates mTORC1
• Anti-catabolic effects are consistent from an evolutionary perspective
• Ketogenic diet inhibits mTOR
• If you want to use a ketogenic state for recovery:
  • Have adequate nutrient availability, caloric intake, and carbs (allows liver and muscle glycogen levels to be full)
  • Include ketone esters with regular meals (induces anabolic pathway not present without ketone esters)
• To trigger autophagy, decrease mTOR, and enhance fasting:
  • Use nutritional ketosis and/or ketone esters
  • Lower amount of carb intake and calorie availability
• Open question of inquiry: Is β-hydroxybutyrate (BHB) itself the signaling molecule that triggers HDAC inhibition, FOXO3, other longevity pathways, or is it the caloric restriction itself?

-Pros and cons of endogenous and exogenous ketosis…24:18

• What's happening physiologically:
  • Endogenous includes carb restriction by default (not necessarily calorie restriction)
  • The brain senses lower AMPK due to a lack of glucose
  • Increases lipolysis and fat mobilization
  • Blood-brain barrier prevents fat from entering to provide substrate for neurons
  • Increase in free fatty acids
  • Fat burning lipolysis
• Exogenous ketosis: eating calories in the form of ketones
• Exogenous ketones will elevate BHB aggressively
• Inhibit lipolysis (fat burning) and free fatty acids go down
• Ketones can be used a metabolic fuel as well as a signaling metabolite
• Ketones mediate ghrelin (the appetite hormone) which signals satiety

-The difference between ketone esters and salts…35:15

• Ketone salt: BHB bound to a mineral (a salt)
• Pros and cons of salts:
  • Cheap and available
  • Often too much mineral in a ketone salt product
• Ketone esters: Organic molecule that has an oxygen double bond between different components (monoesters and diesters)
• Future research will reveal a “family” of esters, similar to carbohydrates, fats, etc.
• H.V.M.N. focuses on a monoester: BHB esterified with R1,3-butanediol
• This ketone ester delivers 100% of BHB vs. ~50% with ketone salts
• Another ketone ester is acetoacetate diester, that Dom D'Agostino has worked on.

-The ketone esters developed by the DARPA program…38:45

• Beginning in the 1960s, various studies conducted to determine the efficacy of ketones
  • Fasting study at Harvard by George Cahill – studies on starvation
  • Dr. Richard Veech, one of the earliest researchers of ketones and understanding the metabolic implications of ketones
  • At the start, a lot of people thought of ketones as metabolic waste products for type 1 diabetics, did not realize the broader implications as a fuel substrate as well as a signaling metabolite
• Early 2000s, DARPA program headed by Dr. Joseph Bielitzki initiates project to determine the human factor in fighting wars
• Quercetin, cooling glove out of Stanford and ketone esters were part of the program
• DeltaG is the code name for a ketone monoester developed in the program
• Last 4-5 years, performance-enhancing aspects of ketones have been studied as part of the program
• Geoffrey's podcast with Dr. Joseph Bielitzki of the DARPA program

-Gold standard usage for dosage and frequency of ketone esters…44:45

• Dosage is based on body weight
• High amounts needed for pre-exercise (for Tour de France cyclists)
• Aim for a threshold of BHB in the blood
• Body becomes more efficient when more adapted to ketones
• Blood BHB is the most important variable—dependent on body weight, metabolism, and keto adaptability
• Ketones uses:
  • Cognitive use (military and sports decision making)
  • Used prior to and after fasting
  • Transition to ketogenic diet minus the “keto flu”
• Blood is the best way to measure ketone levels
• You don't excrete as many ketones when you become keto-adapted

-Whether or not ketones break a fast…53:35

• What is the purpose of the fast
• Which metabolic pathways do we care about
• Ketones are mildly insulinogenic at best
• They do not upregulate the mTOR pathway (only happens when stacked with carbs and protein)
• Ketosis shifts NAD+ and NADH ratio to enhance sirtuin activation

-How a process called lactylation enhances the expression of longevity genes…57:11

• BHB binds histones through process called β-hydroxybutyrylation
• Same thing happens with lactate
• “Biology is a study of snapshots”
• Lactic acid builds up during exercise
• Lactate crosses the blood-brain barrier
• Possible use in treating TBI, concussions, etc.

-Parallels between lactate and ketones…1:02:15

• Not insulin-mediated; substrates for metabolic health
• Cognitive and TBI repair
  • No glucose can be utilized by the brain after a concussion or TBI
• Potential for use treating Alzheimer's, Parkinson's, etc.
• HBOT chamber (use code BEN to save $500)
• Sodium bicarbonate (baking soda) is the best way to buffer lactate

-Stacking sodium bicarbonate with ketone esters pre-workout…1:07:15

• Water, tip of teaspoon (microdosing) leading to the workout helps with potential diarrhea
• Lactigo transdermal carnosine applications (use code BEN to save 20%)

-Ketones used in place of alcohol in cocktails…1:10:15

• 1,3-butanediol can give the buzz minus the toxicity of alcohol
• Anti-anxiety effect demonstrated in animal models
• Butanediols combined with alcohol is highly discouraged
• Minimal sleep disruptions with use of ketones rather than alcohol
• CBD and ketone combinations

-And much more…

Click here for the full written transcript of this podcast episode.

Resources from this episode:

– Geoffrey Woo:

• DeltaG
• H.V.M.N. Podcast with Dr. Joseph Bielitzki of the DARPA program
• H.V.M.N. Blog: 3 Ways to test for ketosis
• “Smart Drugs” documentary

– BGF podcasts and articles on ketones and ketosis:

• All Of Your Burning Keto Questions Answered: Fasting On Keto, Keto For Fat Loss, Keto Nootropics & Supplements, & Much More!
• Ketosis vs. Carnivore Diet, Why Ketosis Isn’t For Everyone, & How To Do Ketosis & Carnivore “The Right Way.”
• KetoFasting: The Dark Side of Fasting & Ketosis (+How To Use Cyclic Ketosis To Fix The Issues).
• Building Muscle On A Ketogenic Diet, Little-Known Keto Mistakes, The Best Supplements For A Ketogenic Diet & Much More!
• The Biggest Common Keto Mistakes (& How to Fix Every Metabolic Problem With A Low-Carb Diet In Just 7 Seconds).
• Why A High-Fat, Ketogenic Diet Chock Full Of Saturated Fat, Coconut Oil & Butter Could Be Destroying Your Brain (& What To Do About It).
• The Keto Reset Diet: Reboot Your Metabolism in 21 Days and Burn Fat Forever.
• Building Muscle & Testosterone On A Ketogenic Diet, Food Combining, Psychedelic Experimentation, Natural Depression Remedies & More!
• How To Maximize Ketosis, Should You Have Sex Before Competition, Do Power Poses Really Work & More.
• Cyclic Ketosis, “Thinkitating,” Bad-Ass Meditation, Morning Routines & More With Quest Nutrition Founder Tom Bilyeu.
• Six-Egg Breakfasts, Ketosis For Bodybuilders, Resetting Weed Tolerance, Kratom Experimentation & Much More With The Mindpump Guys!
• Everything You Need To Know About How To Use Amino Acids For Muscle Gain, Appetite Control, Injury Repair, Ketosis And More.
• Could This Ketosis-Based Elixir Hold The Key To Weight Loss, World Record Performances, Brain Healing, and More?
• A Deep Dive Into Ketosis: How Navy Seals, Extreme Athletes & Busy Executives Can Enhance Physical and Mental Performance With The Secret Weapon of Ketone Fuel
• Which Ketone Supplement Works Best: Ketone Salts vs. Ketone Esters With Dr. Dominic D’Agostino.
• How To Get Into Ketosis In 60 Minutes Or Less (& Which Vitamins, Minerals, Nutrients & More To Fill In The Holes Of A Ketogenic Diet)
• The Official “Ask Me Anything About Ketosis & Ironman” Premium Podcast with Ben Greenfield

– Gear and supplements:

• H.V.M.N. Ketones
• HBOT chamber (use code BEN to save $500)
• LactiGo Carnosine (use code BEN to save 20%)
• Element Health CBD
• Baking Soda
• Quercetin

– Other resources:

• Crossfit Murph, named after Michael Murphy
• Ketones: The Fourth Macronutrient – an article in the Independent
• Study: Fasting study at Harvard by George Cahill
• Study: Ketogenic diet inhibits mTOR
• Study: Keto-Adaptation and Endurance Exercise Capacity, Fatigue Recovery, and Exercise-Induced Muscle and Organ Damage Prevention: A Narrative Review
• Study: β-Hydroxybutyrate – A Signaling Metabolite
• Dr. Dominic D'Agostino article on Acetoacetate diester

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Do you have questions, thoughts, or feedback for Geoffrey or me? Leave your comments below, and one of us will reply!