Ketosis: Cognitive, Metabolic, and Therapeutic Applications - Episode Hero Image

Ketosis: Cognitive, Metabolic, and Therapeutic Applications

The Tim Ferriss Show · · Listen to Original Episode →
Original Title:

TL;DR

  • Ketosis enhances cognitive function and mood stability by altering brain neuropharmacology, specifically by lowering glutamate and elevating GABA, which has broad applications for psychiatric disorders.
  • Ketogenic diets can promote significant weight loss by reducing insulin levels, shifting metabolism to fat burning, and stimulating ketogenesis, which has broad metabolic and epigenetic signaling applications.
  • The ketogenic diet targets the energy systems of glycolytic microbes like Borrelia (Lyme disease) and augments the adaptive immune response via beta-hydroxybutyrate, aiding in targeting foreign invaders.
  • Metabolic memory suggests that consistent adherence to ketosis enhances mitochondrial function and capacity, allowing for rapid re-adaptation and sustained benefits even after periods of dietary change.
  • Chronic consumption of 1,3-butanediol-based exogenous ketones may lead to liver toxicity, evidenced by elevated transaminases and histological changes, necessitating caution and preference for non-1,3-butanediol formulations.
  • A Glucose Ketone Index (GKI) between 1 and 4 is considered therapeutic for various conditions, indicating a balance between glucose utilization and ketone production, achievable through diet and supplementation.
  • Regular exercise, particularly resistance training, acts as an endocrine organ, producing neuroprotective hormones and molecules, and is crucial for maintaining metabolic health and delaying neurodegenerative diseases.

Deep Dive

Ketosis, a metabolic state achieved through ketogenic dieting or fasting, offers significant benefits for cognitive function, mood stabilization, and metabolic health, with emerging evidence suggesting neuroprotective and anti-inflammatory properties. While often associated with weight loss, its primary value lies in its ability to quiet the mind, enhance mental clarity, and mitigate the debilitating "afternoon dip" common with carbohydrate-rich diets. Furthermore, ketosis offers a therapeutic avenue for a range of neurological and psychiatric conditions, including epilepsy, depression, and bipolar disorder, by altering brain neuropharmacology to promote a calming effect.

The practical application of ketosis, particularly for individuals like Tim Ferriss who have experimented extensively, reveals profound personal benefits. Ferriss describes experiencing reduced sleep needs, enhanced mental sharpness, and a remarkable stabilization of mood, particularly minimizing negative emotional swings. This personal experience extends to a compelling anecdotal case where strict ketosis led to the remission of severe cognitive and physical symptoms following Lyme disease, suggesting a potential mechanism involving targeting the glycolytic energy systems of pathogens and augmenting the immune response. This highlights ketosis not just as a dietary choice but as a potential therapeutic intervention for specific conditions.

Beyond cognitive and mood benefits, ketosis demonstrates efficacy in weight management by lowering insulin levels and promoting fat burning, leading to significant scale changes. For individuals with insulin resistance, this metabolic shift is crucial. The exploration of exogenous ketones, while popular, introduces complexities regarding toxicity and appropriate usage. Dr. Dominic D'Agostino emphasizes that while exogenous ketones can temporarily elevate blood ketone levels, their long-term use, particularly those derived from 1,3-butanediol, poses risks of liver toxicity and potential dependence. This underscores the importance of understanding the source and formulation of exogenous ketones and prioritizing endogenous ketone production through diet and fasting for sustained health benefits.

The concept of "metabolic memory" suggests that periods of ketosis can confer lasting physiological adaptations, enhancing metabolic flexibility and improving the body's ability to utilize fat for energy even after transitioning away from a strict ketogenic diet. This is analogous to muscle memory in athletic training, where prior conditioning facilitates quicker returns to peak performance. Regular, periodic engagement with ketosis, even for short durations, may therefore offer enduring protective effects against age-related chronic diseases, including neurodegenerative conditions like Alzheimer's.

The benefits of ketosis are not solely dependent on achieving extremely high ketone levels. For many, a moderate approach, focusing on a low-carbohydrate diet with periodic deeper ketotic states, may offer approximately 80% of the benefits. The "sweet spot" for therapeutic ketosis appears to be between 1-2 millimolar of beta-hydroxybutyrate, promoting metabolic health and signaling effects without the potential downsides of energy toxicity. Furthermore, integrating other lifestyle factors such as regular exercise, adequate hydration, and sufficient sleep, alongside dietary interventions, is critical for optimizing overall health and brain function.

The discussion also touches upon the potential for ketosis to support individuals with certain cancers by slowing tumor growth, particularly in highly glycolytic cancers, and enhancing the efficacy of standard treatments. However, it is crucial to note that ketosis is not a cure for cancer but a complementary therapy. Similarly, for neurodegenerative diseases, optimizing cardiometabolic and immune biomarkers, alongside a ketogenic diet, appears to be a promising strategy for delaying onset and improving brain health. This holistic approach, combining diet, exercise, and monitoring key health indicators, is fundamental to long-term well-being.

Action Items

  • Audit exogenous ketone supplements: Identify and avoid products containing 1,3-butanediol due to potential toxicity and dependency risks.
  • Implement a "metabolic memory" strategy: Engage in 1-week ketogenic interventions quarterly, preceded by 2 days of mild caloric restriction, to enhance metabolic flexibility and long-term benefits.
  • Track cognitive performance metrics: Establish baseline cognitive function (e.g., reaction time, decision-making) via standardized tests and re-evaluate quarterly to measure the impact of dietary interventions.
  • Optimize dietary fiber intake: Incorporate daily servings of broccoli and wild blueberries to support gut health and manage glycemic response without compromising ketosis.
  • Calibrate continuous ketone monitoring: If using continuous monitors, regularly calibrate readings with finger-prick blood ketone measurements to ensure accurate data interpretation.

Related Episodes

Key Quotes

"Well there are a few things immediately I will notice once I get to a certain concentration in my blood and that's generally around let's just call it 0.7 millimolars measured with a finger prick and then more as you get going I need less sleep so instead of 8 to 9 hours 6 hours 6 and a half hours I wake up and I am wide awake so that's another difference I wake up and I am wide awake alert ready to go I don't need an hour of booting up and tons of caffeine to get online I am mentally sharper my verbal acuity my ability to think just has a faster turnover and in the afternoons I do not have what you would typically associate with say a normal diet involving lots of carbohydrates the afternoon dip I don't need a nap I don't need a huge extra cup of coffee around two or three in the afternoon to keep me going that is just unnecessary altogether but those all pale in comparison to the mood stabilizing and enhancing effects it just takes the ups and downs and maybe this is peculiar to me but it preserves the ups right I'm not going through crazy manic swings but it doesn't mute your upside in terms of mood but it really stabilizes and minimizes the downswings and that in and of itself makes it worth it to me and then there are questions around long term benefits possible neuroprotection anti inflammation anti cancer effects and this conversation with Dom really informed and changed how I think about how I in the future am going to approach ketosis which will still remain in my quiver as something I use regularly."

Tim Ferriss explains that the immediate benefits he notices from ketosis include needing less sleep, increased mental sharpness, and the absence of the typical afternoon energy dip. Ferriss highlights that these physical benefits are surpassed by the mood-stabilizing and enhancing effects, which he finds particularly valuable. He also mentions potential long-term benefits like neuroprotection and anti-inflammatory properties, indicating that this conversation has influenced his future approach to ketosis.

"There are many benefits to being in ketosis and a ketogenic diet if we're going to go there kind of has the benefits of fasting and there are for millennia we know the benefits of fasting without the baggage without the metabolic baggage you know the muscle loss the fatigue obviously you can't live in a you know that level of caloric deficit but in regards to you know the practical applications of it we know that being in a state of ketosis really quiets the mind and I think that has major implications and this was you know from centuries we knew this and now you know over the past decades this has been like a term kind of used and it's backed up by experimental data to show that there's an elevation of GABA obviously it's silencing a broad array of seizures independent of the ideology temporal lobe seizures you know Lennox Gastaut syndrome Dravet syndrome rare forms of epilepsy the ketogenic diet just quiets the brain lowers glutamate and elevates GABA a brain stabilizing calming neurotransmitter and you know that's why people gravitate towards alcohol right the GABAergic effects of alcohol and benzodiazepines so you can sort of in a very gentle way transition your physiology to a state of ketosis which changes the neuropharmacology of your brain to sort of quiet it down and that I think really echoes its broad application for metabolic psychiatry which is everything from major depression to bipolar to schizophrenia to anxiety disorders to anorexia nervosa that's a very interesting and rapidly expanding application of ketosis that's being funded largely by the Bazuki group."

Dr. Dominic D'Agostino explains that a ketogenic diet offers benefits similar to fasting but without the metabolic drawbacks like muscle loss and fatigue. D'Agostino highlights that ketosis calms the mind, which has significant implications, and is supported by experimental data showing elevated GABA, a calming neurotransmitter. He notes that this effect is why people are drawn to alcohol and benzodiazepines, suggesting ketosis offers a gentler way to achieve a similar calming neuropharmacological state, with broad applications in metabolic psychiatry.

"The spirochete Borrelia that spirochete is essentially 100% glycolytic and when you limit glucose availability and glycolysis you are targeting the energy systems of that microbe so that's one thing to think about and it's well established now it wasn't three years ago but a ketogenic diet in particular beta-hydroxybutyrate elevated in the blood stimulates the adaptive immune response and that's essentially your body's ability to target foreign invaders and neutralize them and that has become a rapidly growing area of interest university of Pennsylvania they're doing CAR T therapy and checkpoint inhibitors because of the ketogenic enhancement of the adaptive immune response."

Dr. Dominic D'Agostino theorizes on why ketosis might be effective for tick-borne diseases like Lyme disease. D'Agostino explains that the Borrelia spirochete is highly glycolytic, meaning it relies on glucose for energy, and limiting glucose availability targets this energy system. Furthermore, D'Agostino notes that elevated beta-hydroxybutyrate from a ketogenic diet stimulates the adaptive immune response, which is crucial for targeting and neutralizing foreign invaders, an area of growing interest in cancer therapies.

"The biggest metabolic lever would be you have enhanced insulin sensitivity and I think that has been the focus for example Ben Bikman wrote a book on this and doing hundreds of podcasts on insulin resistance reversing insulin resistance and low carb ketogenic you know being effective for that so that first and foremost your insulin sensitivity is very high your fat oxidation is really high and your glucose disposal is high and if you're in a caloric deficit your ketone uptake is very high we see this quite convincingly you know in older rats where we like gavage where we like tube feed the rats and they're older the ketones get to toxic levels whereas like a younger metabolically fit rodent will dispose of it very quickly same with the couch potato human same with an elite level athlete so when you measure ketones in the blood that's a function of ketone production and ketone utilization and you could have two to five times higher ketone utilization you know with high metabolic fitness."

Dr. Dominic D'Agostino explains that enhanced insulin sensitivity is a primary metabolic benefit of a ketogenic diet, a concept emphasized by researchers like Ben Bikman. D'Agostino states that high insulin sensitivity leads to high fat oxidation and efficient glucose disposal, and in a caloric deficit, high ketone utilization. He uses an analogy of younger, fit rodents versus older ones to illustrate that metabolically fit individuals, like elite athletes, dispose of ketones much faster, meaning blood ketone levels reflect both production and utilization.

"One to two is a high bar I guess a GKI of one to two and I think we've had this conversation back and forth with this group that we're working with in the cancer community the Society for Integrative Metabolic Oncology is a group that we're discussing the GKI and Thomas Seyfried's very adamant about like getting into one to two but I give pushback and say one to four is if you look at the published literature one to four is absolutely 100% therapeutic across not only cancer but also like seizures and everything so I'm going to expand that range to a one to four so what does that mean that would mean that your

Resources

External Resources

Books

  • "The Four Hour Body" by Tim Ferriss - Mentioned as a reference for past dietary experiments and advice.

Articles & Papers

  • "Spark" - Mentioned as an outdated book covering exercise and brain function.

People

  • Dr. Dominic D'Agostino - Guest on the podcast, associate professor at the University of South Florida Morsani College of Medicine, visiting senior research scientist at the Institute for Human and Machine Cognition, researcher on ketogenic diets and metabolic therapies.
  • Dr. Walter Longo - Mentioned for his research on fasting-mimicking diets.
  • Dr. Rhonda Patrick - Mentioned for her research on intermittent fasting.
  • Mark Mattson - Mentioned for his research related to intermittent fasting.
  • Chris Palmer - Mentioned for his work on ketogenic diets and metabolic psychiatry.
  • Diana Tedone - Mentioned as a patient stabilized with ALS through ketogenic diet therapy.
  • Dr. Ben Bikman - Mentioned for his work on insulin resistance and ketogenic diets.
  • Dr. Valter Longo - Mentioned for his research on fasting-mimicking diets.
  • Dr. Patrick Arnold - Mentioned as a collaborator in formulating ketone esters.
  • Dr. Richard Veech - Mentioned as a co-inventor of ketone esters and a mentor.
  • Dr. Henri Bruningrabber - Mentioned as a developer of triester ketone formulations.
  • Dr. Sammy Hashem - Mentioned as a developer of triester ketone formulations.
  • Dr. Annette Bosworth (Dr. Boz) - Mentioned for popularizing the concept of "sardine fasting."
  • Dr. Donald Layman - Mentioned as a proponent of protein intake in the morning.
  • Dr. Stu Phillips - Mentioned as a proponent of protein intake in the morning.
  • Dr. Lane Norton - Mentioned as a proponent of protein intake in the morning.
  • Dr. Mary Newport - Mentioned for a case report involving 1,3-butanediol.

Organizations & Institutions

  • University of South Florida Morsani College of Medicine - Affiliation of Dr. Dominic D'Agostino.
  • Institute for Human and Machine Cognition - Affiliation of Dr. Dominic D'Agostino.
  • NASA - Mentioned in relation to Dr. D'Agostino's research as a crew member on extreme environment missions.
  • Office of Naval Research - Mentioned as a supporter of Dr. D'Agostino's research.
  • Department of Defense - Mentioned as a supporter of Dr. D'Agostino's research.
  • NIH (National Institutes of Health) - Mentioned as a supporter of Dr. D'Agostino's research.
  • Bazuki Group - Mentioned as a funder of research in metabolic psychiatry.
  • University of Pennsylvania - Mentioned for research in CAR T-cell therapy and checkpoint inhibitors related to ketogenic enhancement of the immune response.
  • Harvard - Affiliation of Dr. Chris Palmer.
  • CDC (Centers for Disease Control and Prevention) - Mentioned in relation to Lyme disease testing.
  • Exploding Kittens - Mentioned as the team behind the card game "Coyote."
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example team for performance analysis.
  • Pro Football Focus (PFF) - Mentioned as a data source for player grading.
  • National Football League (NFL) - Mentioned in the context of sports analytics.
  • New England Patriots - Mentioned as an example

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