Let's start with a question. When do people rely on their cognitive abilities the most? Of course, we would get many different answers from various people these days. Some might say university exam, others might mention job interview or important business meeting. However, if you would travel back in time, before the agricultural revolution, and ask our ancestors the same question, the answer would probably be mostly "when we need to get food after several days of starvation."
Starvation is a challenging time for our body and the brain. The size of our brains distinguishes us from the rest of the animal kingdom. However, with a great brain comes a great energy demand - the brain consumes over 20% of our overall energy needs. When we eat enough carbohydrates, our brain uses glucose as fuel. While our body has large fat stores, we do not store a lot of glucose. This is a problem because, unlike muscles, our brains can not be fuelled by fat. If our brain had to survive only with the glucose stored around the body, we would die after 3-5 days of starvation.
Indeed, humans can survive much longer than that because the stored fat can be converted into ketones in the liver during starvation. Ketones are secreted into the bloodstream and used as an energy source by the brain. When our ancestors starved and needed their cognitive abilities the most to obtain food, their blood ketone levels were elevated.
Intriguingly, science starts to elucidate that ketones are not only a mere substitution for glucose. Instead, ketones are part of the evolutionary adaptations that help us deal with starvation. Ketones helped our ancestors to survive starvation by providing energy and enhancing their cognitive abilities, making them better hunters and foragers.
While we no longer need to hunt, executives, soldiers, and athletes drink deltaG to boost their energy and support their cognition in various scenarios. In this blog, we will show you studies demonstrating that ketones improve cognitive abilities, provide energy to neurons and prevent the deterioration of brain function that comes with ageing.
The ability of ketones to become a source of energy for our neurons makes it fundamentally different from other stimulants. Stimulants like caffeine must "cheat the system" to have the stimulatory effect. For example, caffeine blocks receptors of adenosine, a molecule which makes us tired. While the blockage has a stimulatory effect for a while, more adenosine accumulates in the meantime. The stimulatory effect is inevitably followed by a crush in energy as the blockage of adenosine receptors wears off, and the accrued adenosine starts to make us tired.
Ketones do not need to "cheat the system" to give us an energy boost because ketones are literally the source of energy. Ketones travel to the mitochondria, the cellular powerplant, where they are oxidised and create an ATP molecule which fuels the energy-intensive processes in our brain, such as neuronal communication. β-hydroxybutyrate (BHB), the ketone body elevated after drinking deltaG, improves the efficiency of mitochondrial ATP production by 28% compared to glucose1. Moreover, BHB also stimulates neuronal metabolism2 and decreases oxidative stress3,4. These biochemical properties make BHB a great source of energy for our brains.
Because ketones do not need to “cheat the system”, the energy from deltaG is sustained, and you don’t crush once ketones are used up by our cells. Moreover, the energy from ketones also comes without any jitters or agitation. Most of the available stimulants increase our blood pressure, cause heart palpitation or arrhythmia and can affect our sleep5. In contrast, BHB was shown to lower blood pressure6 and shows promise as a cardioprotective compound7. As we will discuss later, BHB might aid sleep quality.
Thanks to MRI scans, we can have a closer look at mechanisms by which ketones improve our cognition and attention. Recently, MRI scans started to be used to assess the network stability of our brains. Several brain regions control different functions like vision, hearing, problem-solving or spatial awareness. These regions do not work in isolation. To process information, they constantly communicate with each other and create networks. Network stability refers to the ability of brain regions to sustain communication with each other.
To use an analogy, we can imagine our brain as a room where two people try to talk to each other. A brain with high network stability is like a quiet room where communication is easy. Conversely, low network stability would refer to a room with loud music where it is challenging to talk with each other.
In a 2019 study8, researchers revealed that people who achieve a higher score on intelligence tests have higher brain network stability. Brain regions of people with higher intelligence communicate easier with each other. The stability of networks in brain regions responsible for controlling attention was especially important for intelligence. The study concluded that the ability to focus is a crucial determinant of general intelligence. We also know that brain network stability decreases since the late 40' and that a sharp decline in network stability comes when we are 609.
A study9 from 2020 investigated if brain network stability responds to two major brain fuels – glucose or ketones. Participants came to the laboratory on two occasions and drank either 25-30 grams of deltaG or 30-35 grams of glucose. After consumption of these drinks, they underwent an MRI scan. Strikingly, the study showed that ketones increased the stability of brain networks. In contrast, glucose decreased the stability of the network. The network stability was 87% greater after ketone consumption than stability measured after glucose consumption.
This objective scientific observation of increased brain network stability agrees with the subjective experience of people who consume deltaG. They often describe that deltaG makes it much easier for them to get to the flow state, colloquially termed "the zone". The flow state represents a state of full involvement and energised focus, an ideal mental state for increased productivity. The ability of deltaG to increase the stability of brain networks and make communication between brain regions more streamlined might make reaching the flow state easier.
There are multiple studies which demonstrated that deltaG increases our cognitive abilities both during rest and during exercise. A 2021 study10 recruited 14 adults who consumed 12 grams of deltaG thrice daily for 2 weeks. Participants completed a cognitive test that assessed processing speed, working memory, visuospatial processing, and attention before and after the 2 weeks of deltaG consumption. The deltaG consumption led to a 6% improvement in the cognitive test.
Moreover, researchers also reported that deltaG increased cerebral blood flow, the amount of blood delivered to the brain. Interestingly, participants who showed a higher increase in cerebral blood tended to achieve greater improvement in the cognitive test, which suggests that the increase in cerebral blood flow might be responsible for the boost of cognition.
A 2020 study11 showed that it is not necessary to consume ketones for 2 weeks to see an improvement in cognitive abilities. Patients with type 2 diabetes received infusion, which increased blood BHB levels to ~2.5mM, similar levels as achieved by drinking deltaG. Participants completed a test assessing work memory and information processing before the infusion and after the infusion. They achieved, on average, a 17% improvement in the cognitive test.
Finally, a recent 2022 study12 reported that deltaG improved mental performance during exercise. On two separate occasions, participants underwent cognitive assessments during exercise – with or without drinking deltaG. First, they completed mentally draining tasks for 40 minutes to induce mental fatigue. Then, participants performed 45 minutes of high-intensity, intermittent exercise that resembled a soccer game. Before the exercise began, participants completed one session of a reaction test and another six sessions of a reaction test followed during the exercise. As expected, exercise reduced performance in the reaction test. However, the performance in the reaction test after drinking deltaG declined only by 1.3%, while performance decreased by 3.4% without deltaG.
The ability of ketones to affect brain function translate not only into improved cognition but can also protect our brains from age-related deterioration. The prevalence of dementia is rising all over the developed world. Despite billions of dollars invested in dementia research, researchers are yet to devise reliable ways to stop cognitive decline once it occurs. Instead, the focus shifts to prevention. We know that measurable signs of brain health deterioration occur 10-15 years before the onset of memory symptoms13.
One of the early signs of brain deterioration is a reduced ability to use glucose as a source of energy. Researchers showed that an aged brain uses much less glucose than a young brain14. As a result, the brain starts to starve, and neurons progressively degenerate. The decrease in brain glucose uptake is associated with insulin resistance, which explains why people with type 2 diabetes have a significantly elevated risk of developing Alzheimer's disease15.
A 2016 study16 showed that ketones might solve the problem of a starving brain. While glucose uptake into the brain was impaired in both cognitively healthy older people and people with mild cognitive impairment, the uptake of ketones was not disrupted. Ketones can rescue the starving brain and provide an alternative fuel, similar to ketone’s role during starvation.
However, most people's diet is too high in carbohydrates which block the endogenous production of ketones, and the brain remains starved. Therefore, supplying the brain with exogenous ketones is a viable way to fuel your brain and prevent the damage caused by neuronal energy deficits. Moreover, as described in our blog about deltaG's potential to improve metabolic health, deltaG improves insulin resistance which might help to restore brain glucose uptake.
Besides decreased glucose uptake, our brain also receives less blood as we age. Such deterioration does not affect only the delivery of glucose or oxygen but also other micronutrients essential for brain function. As mentioned above, two weeks of deltaG consumption increased cerebral blood flow10. Therefore, ketones might not only provide fuel to the brain but also increase the rate of delivery of the fuel.
Once ketones or glucose are delivered to the neuron, they are oxidised in the mitochondria. Mitochondrial health is imperative for brain function because the communication between neurons is energy intensive. Mitochondria are prone to damage because oxidation of metabolic fuels generates oxidative stress. As we age, our capacity to repair and restore mitochondria diminishes. Studies showed that the neurons of older adults contain fewer and less functional mitochondria than the neurons of young people17.
Ketones might help to preserve mitochondrial health. Firstly, the oxidation of BHB produces less oxidative stress1 and stimulates the activity of our internal antioxidants4. Secondly, a study18 from 2020 showed that deltaG stimulates the expression of protein sirtuin-3 in the cerebral cortex of mice. The human brain also contains sirtuin-3, and we know that this protein stimulates mitochondrial biogenesis19 – the production of new mitochondria. By protecting mitochondria from oxidative stress and inducing the production of new mitochondria, ketones preserve the ability of neurons to generate energy even as we age.
Several pieces of preliminary evidence suggest that ketones might also enhance our sleep. Studies showed that a ketogenic diet could improve several aspects of sleep quality, like increased slow-wave restorative sleep, reduced nocturnal awakenings and reduced daytime sleepiness20.
These positive effects of the ketogenic diet might be brought by ketones. BHB increases synthesis21 and decreases the degradation22 of the neurotransmitter GABA which is known to induce sleep23. Moreover, a study24 with fasting mice showed that BHB might alter the expression of genes which control circadian rhythms via epigenetic mechanisms. Indeed, these genes can significantly affect sleep quality as they regulate the daily oscillations of processes like melatonin secretion or body temperature, which needs to drop during sleep. However, the effect of ketones on human sleep architecture is yet to be elucidated.
- Sato, K., Kashiwaya, Y., Keon, C.A., Tsuchiya, N., King, M.T., Radda, G.K., Chance, B., Clarke, K. and Veech, R.L., 1995. Insulin, ketone bodies, and mitochondrial energy transduction. The FASEB Journal, 9(8), pp.651-658.
- Achanta, L.B., Rowlands, B.D., Thomas, D.S., Housley, G.D. and Rae, C.D., 2017. β-Hydroxybutyrate boosts mitochondrial and neuronal metabolism but is not preferred over glucose under activated conditions. Neurochemical Research, 42(6), pp.1710-1723.
- Norwitz, N.G., Hu, M.T. and Clarke, K., 2019. The mechanisms by which the ketone body D-β-hydroxybutyrate may improve the multiple cellular pathologies of Parkinson's disease. Frontiers in nutrition, 6, p.63.
- Shimazu, T., Hirschey, M.D., Newman, J., He, W., Shirakawa, K., Le Moan, N., Grueter, C.A., Lim, H., Saunders, L.R., Stevens, R.D. and Newgard, C.B., 2013. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science, 339(6116), pp.211-214.
- Seifert, S.M., Schaechter, J.L., Hershorin, E.R. and Lipshultz, S.E., 2011. Health effects of energy drinks on children, adolescents, and young adults. Pediatrics, 127(3), pp.511-528.
- Chakraborty, S., Galla, S., Cheng, X., Yeo, J.Y., Mell, B., Singh, V., Yeoh, B., Saha, P., Mathew, A.V., Vijay-Kumar, M. and Joe, B., 2018. Salt-responsive metabolite, β-hydroxybutyrate, attenuates hypertension. Cell reports, 25(3), pp.677-689.
- Chu, Y., Zhang, C. and Xie, M., 2021. Beta-hydroxybutyrate, friend or foe for stressed hearts. Frontiers in aging, p.16.
- Hilger, K., Fukushima, M., Sporns, O. and Fiebach, C.J., 2020. Temporal stability of functional brain modules associated with human intelligence. Human brain mapping, 41(2), pp.362-372.
- Mujica-Parodi, L.R., Amgalan, A., Sultan, S.F., Antal, B., Sun, X., Skiena, S., Lithen, A., Adra, N., Ratai, E.M., Weistuch, C. and Govindarajan, S.T., 2020. Diet modulates brain network stability, a biomarker for brain aging, in young adults. Proceedings of the National Academy of Sciences, 117(11), pp.6170-6177.
- Walsh, J.J., Caldwell, H.G., Neudorf, H., Ainslie, P.N. and Little, J.P., 2021. Short‐term ketone monoester supplementation improves cerebral blood flow and cognition in obesity: A randomized cross‐over trial. The Journal of Physiology, 599(21), pp.4763-4778.
- Jensen, N.J., Nilsson, M., Ingerslev, J.S., Olsen, D.A., Fenger, M., Svart, M., Møller, N., Zander, M., Miskowiak, K.W. and Rungby, J., 2020. Effects of β-hydroxybutyrate on cognition in patients with type 2 diabetes. European Journal of Endocrinology, 182(2), pp.233-242.
- Quinones, M.D. and Lemon, P.W., 2022. Ketone Ester Supplementation Improves Some Aspects of Cognitive Function during a Simulated Soccer Match after Induced Mental Fatigue. Nutrients, 14(20), p.4376.
- Caselli, R.J. and Reiman, E.M., 2013. Characterizing the preclinical stages of Alzheimer's disease and the prospect of presymptomatic intervention. Journal of Alzheimer's Disease, 33(s1), pp.S405-S416.
- Chakrabarty, R., Yousuf, S. and Singh, M.P., 2022. Contributive Role of Hyperglycemia and Hypoglycemia Towards the Development of Alzheimer’s Disease. Molecular Neurobiology, 59(7), pp.4274-4291
- Suzanne, M., 2009. Insulin resistance and Alzheimer’s disease. BMB reports, 42(8), p.475.
- Cunnane, S.C., Courchesne-Loyer, A., Vandenberghe, C., St-Pierre, V., Fortier, M., Hennebelle, M., Croteau, E., Bocti, C., Fulop, T. and Castellano, C.A., 2016. Can ketones help rescue brain fuel supply in later life? Implications for cognitive health during aging and the treatment of Alzheimer’s disease. Frontiers in molecular neuroscience, p.53.
- Sun, N., Youle, R.J. and Finkel, T., 2016. The mitochondrial basis of aging. Molecular cell, 61(5), pp.654-666.
- Cheng, A., Wang, J., Ghena, N., Zhao, Q., Perone, I., King, T.M., Veech, R.L., Gorospe, M., Wan, R. and Mattson, M.P., 2020. SIRT3 haploinsufficiency aggravates loss of GABAergic interneurons and neuronal network hyperexcitability in an Alzheimer's disease model. Journal of Neuroscience, 40(3), pp.694-709.
- Kong, X., Wang, R., Xue, Y., Liu, X., Zhang, H., Chen, Y., Fang, F. and Chang, Y., 2010. Sirtuin 3, a new target of PGC-1α, plays an important role in the suppression of ROS and mitochondrial biogenesis. PloS one, 5(7), p.e11707.
- Masi, D., Spoltore, M.E., Rossetti, R., Watanabe, M., Tozzi, R., Caputi, A., Risi, R., Balena, A., Gandini, O., Mariani, S. and Spera, G., 2022. The Influence of Ketone Bodies on Circadian Processes Regarding Appetite, Sleep and Hormone Release: A Systematic Review of the Literature. Nutrients, 14(7), p.1410.
- Newman, J.C. and Verdin, E., 2017. β-Hydroxybutyrate: a signaling metabolite. Annual review of nutrition, 37, p.51.
- Suzuki, Y., Takahashi, H., Fukuda, M., Hino, H., Kobayashi, K., Tanaka, J. and Ishii, E., 2009. β-hydroxybutyrate alters GABA-transaminase activity in cultured astrocytes. Brain research, 1268, pp.17-23.
- Gottesmann, C., 2002. GABA mechanisms and sleep. Neuroscience, 111(2), pp.231-239.
- Cornuti, S., Chen, S., Lupori, L., Finamore, F., Samad, M., Raimondi, F., Mazziotti, R., Magnan, C., Rocchiccioli, S., Baldi, P. and Tognini, P., 2022. Brain histone beta-hydroxy-butyrylation couples metabolism with gene expression. bioRxiv, pp.2021-06.