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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 ketones as a tool for a wide range of applications, 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 use cases, from managing Alzheimer’s disease as an alternate fuel source for the brain to enhancing human longevity as fasting mimetic.

We can credit the explosion of interest within the last five years 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 ketones.

This technology unlocked the ability to study the state of ketosis ‘on-demand.’ Ketone production 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 the equivalent of a 10-day fast in 30 minutes? From a clinical trial management perspective, what if hundreds of people could easily be put in ketosis instead of having to monitor participants to make sure that they aren't cheating on their ketogenic diet during a study? Exogenous ketones unlock a new world of research questions.

Our area of expertise involves exogenous ketones, in particular ketone esters. Before we dive into it, it’s important to understand that ketosis, the presence of ketones in the body and brain, is 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. Anyone from elite performers to researchers to average consumers can start experimenting with ketones, quickly and easily.

There’s been a tremendous amount of speculation about ketone esters, given the massive media, commentator, and even political interest and notoriety during the 2018 and 2019 Tour de France as well as the 2012 British Olympic program. Our goal for this article is to highlight what we personally think are some of the most exciting use cases that are not yet widely discussed or understood. We will also discuss 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, 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. In this article, we’ll focus on applications and protocols from case studies and anecdotes that we have collected 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 in the future.

Use Cases of Ketone Ester

1. Recovery 

While ketone esters are more popularly used to enhance stamina and performance during exercise, early studies and data showed that it may have more potential as an ergogenic for recovery. To date, there are 3 studies that have monitored recovery after exercise following ketone ester consumption (Holdsworth et al., 2017; Poffe et al., 2019; Vandoorne et al., 2017). All 3 studies found some benefit of ketone ester in recovery when taken with recommended macronutrients, such as carbohydrates and protein, after a workout.

The studies' findings can be summarized as follows:

  • Holdsworth et al.: Ketone ester increased glucose uptake, insulin secretion, and glycogen resynthesis in recovery.
  • Vandoorne et al.: When taken with carbohydrates and protein, ketone ester promotes mTORC1 signaling 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 a 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. When taken with protein (especially containing leucine) and glucose, ketone ester does not change glycogen synthesis but instead activates mTOR targets and up-regulates 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 the recovery period is short (e.g. ultramarathons with little to no breaks or military operations that require optimal endurance and output with minimal rest), ketone ester and glucose administration may provide a better fuel option. This strategy can help ensure that glycogen is quickly replenished before the individual needs to expend energy for physical performance again. Otherwise, if given ample amounts of carbohydrate that exceeds the maximum threshold for glycogen storage over 24 hours, glycogen stores will restore to baseline levels (Burke et al., 2004; Ivy et al., 2002). 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 a normal rate while benefiting from the repair and recovery of protein synthesis up-regulation via activation of mTOR.

The current data suggest that only a single dose of ketone ester taken after exercise and before bed is enough to exert the ergogenic effects in recovery. All of 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 that will yield such effects. 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 

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

A number of athletes and groups in these disciplines are looking at ketone esters to facilitate this grueling process.

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 are interesting implications beyond just managing appetite for the weight-cutting process.

Ketone bodies may play a role in different mechanisms to exert their 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 agents on both systemic and skeletal muscle-specific levels, where the reduction of protein breakdown catalyzed 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. When energy is used up after an intense bout of exercise, there will be an energy imbalance in the skeletal muscles. 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). You need to replenish the energy you have lost before your body even begins to initiate repair and recovery. As a result, 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 a reason to suspect that downstream metabolism in neurons is altered from more typical glucose metabolism. This is an increasingly large research area, and we’ve done some early work in this space 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 feeling in-flow after taking ketones. 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 on 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 and social media reports from hobbyists and citizen scientists that ketones before sleep seem to increase HRV, a sign of better parasympathetic response. Ketones may also 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, ketone ester lessened amyloid β-peptide and hyperphosphorylated τ deposition, which reduced 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 central nervous system diseases, especially in humans, are yet to be determined. 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. Ketone esters may help 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 the personal protocols he’s been experimenting with.

The current gold standard combines ketones with carbohydrate protocol pre-endurance bout. This is the protocol that Vittoria Bussi used in her race nutrition strategy when she set the World One-Hour Cycling Record in 2018. We help various athletes experiment with other additions, such as stacking caffeine as well as buffers like sodium bicarbonate, leading to positive anecdotal results. This data is still very limited, and the mechanisms may be speculative.

However, a recent study found that bicarbonate levels were decreased after exercise and ketone ester ingestion (Poffe et al., 2020). 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 stacking ketones 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. 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.

In terms of the brain, there is early work trying to understand how one might be able to apply ketones to brain insults like a traumatic brain injury. However, there's still more research to explore. Interventions like hyperbaric oxygen therapy and Omega-3’s and more exotic derivatives of Omega-3’s like Specialized Pro-resolving Mediators (SPM) have been examined on a standalone basis, and there seem to be overlapping mechanisms suggesting synergy in combination with ketones. There have also been whispers with people experimenting with plant medicines and other psychoactive substances in conjunction with ketosis as well. There is much 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 the effects of ketone esters on both organ-specific functions and a systemic level, more and more researchers and enthusiasts are venturing into using exogenous ketones as potential nutritional therapy for different diseases. These applications include diabetes, cardiovascular disease, Alzheimer’s disease, and certain types of cancers (as supplementation to chemotherapy).

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

  • Human performance
    • Determining the optimal level of exogenous ketones and ideal combinations of nutrients and supplements 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
    • Research on the role of ketones (both endogenous and exogenous) in aging and investigating the mechanisms that drive 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 a 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.




     

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