Menu
Icons/Close/Hover Created with Sketch.

By Geoffrey Woo, Co-founder and Dr. Latt Mansor, Research Lead

July 20, 2020

Recently Co-founder of HVMN, Geoffrey Woo was on the Ben Greenfield Fitness Podcast to discuss everything ketone-related. Geoffrey and Dr. Latt Mansor co-authored this article in conjunction to the podcast to share the deep knowledge and understanding of all things ketone and the area of research in this exciting field.

Introduction

Ketosis is one of the most active research areas in human metabolism and physiology today. Research groups are actively investigating ketosis as a tool for a wide range of indications, from Type 2 diabetes remission to enhancing human athletic performance. We’re now starting to uncover and unpack the underlying mechanisms of this metabolic state that may lead to new strategies, from better managing Alzheimer’s as an alternate fuel source for the brain to enhancing human longevity as a fasting mimetic. 

This explosion of interest within the last five years can largely be credited to two factors:

  1. the work of early tastemakers Dom D’Agostino, Ben Greenfield, Peter Attia, Tim Ferriss and Joe Rogan making decades of metabolism research accessible for casual enthusiasts and practical for fitness hobbyists, and
  2. the introduction of commercially-available and (relatively) cheap exogenous ketones as a novel tool to further probe the intricacies of the biochemistry and metabolism of ketosis.

This technology unlocked the ability to study the state of ketosis ‘on-demand.’ The metabolic state of ketosis is no longer inextricably intertwined with a ketogenic diet. We can now ask questions like what if ketones could be mixed with a high carb diet? What if ketones could be spiked to equivalent to 10 days fasted in 30 minutes? From a clinical trial management perspective, what if hundreds of people could easily be put in ketosis vs. the struggle of regulating that everyday people aren’t cheating on their ketogenic diet for a study? Exogenous ketones unlock a new world of research questions. 

Our area of expertise is exogenous ketosis, in particular ketone esters. Before we dive into it, it’s important to define ketosis, the presence of ketones in the body and brain, as a separate concept from ketogenesis, the endogenous production of ketone bodies from the liver. These concepts are conflated in older literature because there was no way to reach ketosis without going through endogenous ketogenesis. However, with the commercial availability of exogenous ketones like ketone esters and ketone salts, it is now generally accessible for anyone from elite performers to researchers to average consumers to start experimenting with ketosis, quickly and easily.

There’s been a tremendous amount of speculation about ketone esters, given the massive media, commentator, and even political interest given the notoriety in the 2018 and 2019 Tour de France as well as 2012 British Olympic program. Our goal for this article is to highlight what we personally think is some of the most exciting use cases that are not yet widely discussed or understood and suggest protocols and experiments at the very bleeding edge of what is known about ketone esters.


History

Ketone esters were broadly introduced into the commercial market by H.V.M.N. in 2017, and the product was based on the work initiated by DARPA in 2003. The commercial availability of ketone esters accelerated a number of research programs, sports practices, and hobbyist experimentation. While many of the original DARPA awardees focused on therapeutic applications of ketone esters, groups at Oxford University, Bath University, and KU Leuven investigated the possibility of ketone esters enhancing human performance. Early data describing an ergogenic effect of ~2% (Cox et al.) is well known in sports nutrition, so we’ll focus on applications and protocols that derive from case studies and anecdotes collected from our experience as practitioners and consultants for some of the world’s best athletes and performers. At the cutting edge, there aren't any randomized-controlled trials and the goal of this article is not to claim as such. We simply present insights to serve as a potential signal beacon for more formal research to be done:

Use Cases of Ketone Ester

1. Recovery 

    While ketone esters are more popularly applied for an ergogenic effect during exercise, early studies and data showed that it may have more potential as an ergogenic for recovery. To date, there are 3 studies so far that monitored recovery after exercise following ingestion of ketone ester (Holdsworth et al., 2017; Poffe et al., 2019; Vandoorne et al., 2017). All 3 studies find some form of benefit of ketone ester in recovery when taken with recommended macronutrients such as carbohydrate and protein after workout. The summary of the findings of these studies is as follows:

    • Holdsworth et al. - ketone ester increased glucose uptake, insulin secretion and glycogen resynthesis in recovery
    • Vandoorne et al. - ketone ester when taken together with carbohydrates and protein, promotes mTORC1 signalling in recovery following exercise
    • Poffe et al. - ketone ester prevented overreaching symptoms and helped athletes improve performance over the course of 3 weeks when used as recovery intervention

    Based on the data thus far, we can conclude that ketone ester when taken together with glucose only, may increase insulin secretion, glucose uptake and glycogen synthesis while ketone ester taken with protein (especially containing leucine) and glucose does not change glycogen synthesis but instead activate mTOR targets and upregulate leucine-mediated protein synthesis. 

    So where does that leave us in terms of application? How would we use this information to augment our current nutritional strategy? In situations where recovery period is short (e.g. ultramarathon with minimal breaks between segments or military use cases that needs optimal endurance and output with minimal rest), ketone ester and glucose administration may provide a better option to ensure that glycogen is replenished in a shorter amount of time before the individual needs to expend energy for physical performance again. Otherwise, if given ample amounts of carbohydrate that exceeds the threshold of maximal glycogen storage over 24 hours, glycogen stores will replete itself to baseline levels (Burke et al., 2004; Ivy et al., 2002). Therefore, for a better nutritional strategy for recovery, ketone ester with glucose and protein would be a better option as you will still replenish your glycogen levels at normal rate, while benefiting from the repair and recovery of protein synthesis upregulation via activation of mTOR.

    The current data suggests that only a single dose of ketone ester taken after exercise and before bed is enough to exert the ergogenic effects in recovery and all the studies achieved >4 mM blood BHB following ketone ester ingestion.  However, further studies may be needed to determine the minimal dose of exogenous ketones to achieve the threshold of blood BHB to have such effects, and if there is a minimum concentration of blood BHB to achieve such feat, what would the drop off point be as blood BHB concentrations gradually return to baseline levels.

    2. Anti-catabolic applications and weight cutting 

      A peculiar artifact in sports is the concept of weight classes. From combat sports like wrestling or MMA to sports that depend on power to weight ratio like powerlifting and rowing, there’s a whole new dimension to the game of managing and optimizing weight. How does one lose as much weight as possible on a day, and rejuvenate the next day to obtain a size and weight advantage over the competition? All without becoming so drained and weak that one is rendered ineffective.

      There’s been a number of athletes and groups in these disciplines looking at ketone esters to make this grueling process easier.

      Ketone esters were shown to suppress appetite through ghrelin (Stubbs, 2018) and reducing appetite is obviously valuable. This insight also suggests why some advocates claim that a ketogenic diet is more satiating than a standard Western diet. But there’s interesting implications beyond just managing appetite for the weight cutting process. 

      Ketone bodies may play a role in different mechanisms to exert its anti-catabolic effects. Firstly, ketone bodies can suppress the rates of protein breakdown to cater for gluconeogenesis (production of glucose from non-carbohydrate precursors such as proteins) in starvation (Cahill, 2006; Owen et al., 1967). Thomsen et al. also suggested that ketone bodies play a vital role as potent anti-catabolic agent on both systemic and skeletal muscle-specific levels, where the reduction of protein breakdown catalysed by BHB overrides inhibition of synthesis (Thomsen et al., 2018). Secondly, ketone bodies may increase protein synthesis via mTOR activation. Vandoorne et al. showed that 1 g·kg−1 BW·h−1 carbohydrates (65% maltodextrin, 35% dextrose) plus 0.3 g·kg−1 BW·h−1 hydrolyzed whey-protein concentrate, taken together with 0.5 g·kg−1 BW ketone esters activate leucine-mediated protein synthesis and mTOR downstream targets. Following an intense bout of exercise, as energy has been used up, there will be an energy imbalance in the skeletal muscles and this is regulated by AMP-activated protein kinase (AMPK). The energy balance in skeletal muscles needs to be restored before mTOR activation can take place to upregulate protein synthesis (Dreyer et al., 2006). A simple understanding is that you need to replenish the energy you have lost before your body even begins to initiate repair and recovery. Therefore, ketone ester ingestion for recovery may provide the additional substrate that increases oxidative ATP generation and subsequently decreases AMPK activation to allow protein synthesis

      3.Cognitive and sleep applications

        The impact of ketones on the brain is an exciting experimental area. Because ketones cross the blood-brain barrier and the brain readily metabolizes BHB, there is definitely reason to suspect that downstream metabolism in neurons is altered from a more typical glucose metabolism. This is an increasingly big research area and we’ve done some early work in this area in collaboration with the US military. 

        One of the more interesting anecdotal cases is the use of ketones as an anxiolytic ahead of big presentations or talks. Many users talk about being more present or being more in flow. For example, Dr. Rhonda Patrick on the Joe Rogan podcast has talked about using H.V.M.N. Ketone Ester before taping her own podcast. There’s been a number of animal studies in this area that propose mechanisms, but nothing has yet been formally published in humans.

        There’s been increasing use of ketones as a sleep tool. Some elite Tour athletes have been using half a ketone ester drink right before bed as part of their recovery protocol. We’ve collected numerous anecdotal reports and social media reports from hobbyists and citizen scientists that ketones before sleep seem to increase HRV, a sign of better parasympathetic response, and increase deep sleep scores as tracked by sleep tracking devices like the Oura ring. 

        Part of the sleep boost could be related to the anxiolytic effect. Other mechanisms include modulation of GABAergic, glutamatergic, and adenosinergic systems by ketone bodies.  In a mouse model of Alzheimer’s disease, the ketone ester lessened amyloid β-peptide and hyperphosphorylated τ deposition, which lessened anxiety and improved cognition (Kashiwaya et al., 2013). The specific metabolic pathway changes by ketone bodies associated with the nervous system, leading to benefits in CNS diseases especially in humans are yet to be determined and further studies can be heavily influenced by model-, dose-, method- and regimen-dependent variables. Nonetheless, this area of research is very exciting as mental health has always been overlooked and ketone esters provide a great addition to further refine the nutrition modulation strategies on brain metabolism and diseases.

        4. Ketone stacks

          A lot of the most adventurous and experienced ketone users are creating and experimenting with ketone stacks. In my conversation with Ben Greenfield, he brings up some of his personal protocols he’s been experimenting with.

          The current gold standard that combines ketone with carbohydrate protocol pre endurance bout. This is the protocol that Vittoria Bussi used for her race nutrition for her World Record in the Hour she set in 2018. We help various athletes experiment with other additions like stacking caffeine as well as buffers like sodium bicarbonate to good anecdotal effect. The data for this is still very limited and the mechanisms may be speculative but in a recent study, bicarbonate levels were decreased after exercise and KE ingestion (Poffe et al., 2020), so the hypothesis is adding some form of bicarbonate along the administration of KE may help with acidity caused by the rise in blood BHB and help improve performance. There might be further value to reap by further stacking with other known ergogenics or nootropics like nicotine. In terms of recovery, adding ketones on top of gold standard carbohydrates and protein seems increasingly justified. It stands to reason that there’s much exploration left to find the optimal ratios of carbohydrates and proteins and what forms of each might work for different types of recovery profiles that an athlete is targeting.

          In terms of the brain, there’s so much to be explored and there is early work trying to understand how one might be able to apply ketones to brain insults like traumatic brain injury. Interventions like hyperbaric oxygen therapy and Omega-3’s and more exotic derivatives of Omega-3’s like Specialized Proresolving Mediators (SPM) have been explored on a standalone basis, and there seems to be overlapping mechanisms suggesting synergy in combination with ketones. There’s also been whispers with people experimenting with plant medicines and other psychoactive substances in conjunction with ketosis as well. Much experimentation and research to be explored in this area of the brain, ketones, and stacks. 


          Future research areas

          While the field’s come a long way, we’re still in the very early innings of the ketone ester story. As we discover effects of ketone esters in affecting not only organ-specific functions but also on a systemic level, more and more researchers and enthusiasts are venturing into using exogenous ketones as potential nutritional therapy for different diseases including diabetes, cardiovascular disease, Alzheimer’s disease and certain types of cancers (as a supplementation to complement chemotherapy). 

          We predict and anticipate future studies will fall into these categories of research:

          • Human performance
            • Determining the optimal level of exogenous ketones and, ideal combinations of nutrients and supplements for performance, for performance enhancement, both physically and cognitively.
            • Effects of exogenous ketones on recovery and its mechanisms including protein and glycogen resynthesis, sleep, growth hormone, IGF-1 and other endocrine markers
          • Longevity and well being
            • Continual research to be done on role of ketones (both endogenous and exogenous) in  aging and investigating the mechanisms that drives healthy aging from transcription to translation and downstream cascade of pathways, including the role of betahydroxybutyrlation, where BHB impacts DNA structure in an analogous way as methylation and acetylation.
            • Role of ketones in long term inflammation suppression and antioxidative action 
          • Therapeutic intervention for diseases
            • Glycemic control in diabetes and role in achieving sustainable diabetes remission
            • Role of ketones as preventative therapy for neurodegenerative diseases as data showed ketones may improve brain network stability in young adults (Mujica-Parodi et al., 2020)
            • Elucidate the energy-substrate flux with exogenous ketones in patients with heart failure
            • Determine the mechanism of action of exogenous ketones in complementing chemotherapy and in reducing its side effects

          Author Notes:

          Geoffrey Woo is co-founder of H.V.M.N. — Health Via Modern Nutrition and launched the first commercially available ketone ester product in 2017. He works closely with some of the world’s top performers and athletes with their ketone ester protocols.

          Dr. Latt Mansor is Research Lead of H.V.M.N. — Health Via Modern Nutrition. He earned his DPhil in Physiology, Anatomy and Genetics from University of Oxford and Masters in Biotechnology from Columbia University. His past experience includes academia, pharmaceutical, and healthcare startups across US, UK, Germany, Singapore, Malaysia and Thailand. 


          Reference

          Burke, L.M., Kiens, B., and Ivy, J.L. (2004). Carbohydrates and fat for training and recovery. J Sports Sci 22, 15-30.

          Cahill, G.F., Jr. (2006). Fuel metabolism in starvation. Annu Rev Nutr 26, 1-22.

          Cox, P.J., Kirk, T., Ashmore, T., Willerton, K., Evans, R., Smith, A., Murray, A.J., Stubbs, B., West, J., McLure, S.W., et al. (2016). Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metab 24, 256-268.

          Dreyer, H.C., Fujita, S., Cadenas, J.G., Chinkes, D.L., Volpi, E., and Rasmussen, B.B. (2006). Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle. J Physiol 576, 613-624.

          Holdsworth, D.A., Cox, P.J., Kirk, T., Stradling, H., Impey, S.G., and Clarke, K. (2017). A Ketone Ester Drink Increases Postexercise Muscle Glycogen Synthesis in Humans. Med Sci Sports Exerc 49, 1789-1795.

          Ivy, J.L., Goforth, H.W., Jr., Damon, B.M., McCauley, T.R., Parsons, E.C., and Price, T.B. (2002). Early postexercise muscle glycogen recovery is enhanced with a carbohydrate-protein supplement. J Appl Physiol (1985) 93, 1337-1344.

          Kashiwaya, Y., Bergman, C., Lee, J.H., Wan, R., King, M.T., Mughal, M.R., Okun, E., Clarke, K., Mattson, M.P., and Veech, R.L. (2013). A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer's disease. Neurobiol Aging 34, 1530-1539.

          Mujica-Parodi, L.R., Amgalan, A., Sultan, S.F., Antal, B., Sun, X., Skiena, S., Lithen, A., Adra, N., Ratai, E.M., Weistuch, C., et al. (2020). Diet modulates brain network stability, a biomarker for brain aging, in young adults. Proc Natl Acad Sci U S A 117, 6170-6177.

          Owen, O.E., Morgan, A.P., Kemp, H.G., Sullivan, J.M., Herrera, M.G., and Cahill, G.F., Jr. (1967). Brain metabolism during fasting. J Clin Invest 46, 1589-1595.

          Poffe, C., Ramaekers, M., Van Thienen, R., and Hespel, P. (2019). Ketone ester supplementation blunts overreaching symptoms during endurance training overload. J Physiol 597, 3009-3027.

          Poffe, C., Ramaekers, M., Bogaerts, S., and Hespel, P. (2020). Exogenous ketosis impacts neither performance nor muscle glycogen breakdown in prolonged endurance exercise. J Appl Physiol (1985) 128, 1643-1653.

          Stubbs, B.J., Cox, P.J., Evans, R.D., Cyranka, M., Clarke, K., and de Wet, H. (2018). A Ketone Ester Drink Lowers Human Ghrelin and Appetite. Obesity (Silver Spring) 26, 269-273.

          Thomsen, H.H., Rittig, N., Johannsen, M., Moller, A.B., Jorgensen, J.O., Jessen, N., and Moller, N. (2018). Effects of 3-hydroxybutyrate and free fatty acids on muscle protein kinetics and signaling during LPS-induced inflammation in humans: anticatabolic impact of ketone bodies. Am J Clin Nutr 108, 857-867.

          Vandoorne, T., De Smet, S., Ramaekers, M., Van Thienen, R., De Bock, K., Clarke, K., and Hespel, P. (2017). Intake of a Ketone Ester Drink during Recovery from Exercise Promotes mTORC1 Signaling but Not Glycogen Resynthesis in Human Muscle. Front Physiol 8, 310.




           

          Editors Choice

          Atoms / Icons / List / Back / Black Created with Sketch.
          Support
          Icons/Close/Hover Created with Sketch.

          Help Center

          We’re on a mission to help you. Let us know how we can best assist you!

          Need to get in touch?

          Our team will get back to you in one business day, and often times, much faster.

          (Mon-Fri, 10 AM - 5 PM PST)

          Call us: 1 (833) 415-4866

          Email is: care@hvmn.com

          Cart
          Icons/Close/Hover Created with Sketch.

          Your cart is empty!

          You haven't added anything to your cart yet! Go ahead and check out our products. Then you can come right back to checkout.

          Shop All Products