Ketogenic Diet and the Brain- a brief literature review
The topic of ketogenic diets used therapeutically are not a new concept for me. I have been interested in carbohydrate manipulation since I first tried the Atkins diet when I was 19 years old. Having a long struggle with my weight and insulin resistance, my body always responded well on a lower, but not zero carbohydrate diet. When my carbs dropped too low, I noticed I lacked energy and had trouble focusing, and inability to maintain exercise endurance. I took it upon myself to understand how insulin was involved in body weight regulation, and have had very good success with a more cyclical ketogenic approach, due to my higher activity levels. I studied the works of Lyle McDonald, John Berardi, Tom Venuto, Leigh Peele, Ann Louise Gittleman, and Jade Teta over the past 15 years which shaped my approach in the weight loss industry. I also personally have had great success with prolonged water fasting and was able to significantly reduce inflammation and modulate my immune system with a 5 days water fast. However, I learned there is a tipping point, and I got very sick conducting a 7-day water fast too soon after. I have learned over the years that the approach is certainly individualized and many factors must be taken into consideration when administering ketogenic diets therapeutically.
The articles provided in the module I focused on were the following: (I also referenced other articles as well)
- Diet Mimicking Fasting Promotes Neuro Regeneration
- Ketones Prevent Synaptic Dysfunction by Supporting Mitochondria
- Ketones Reduce Glutamate
- Blog article: The Fat Fueled Brain: Unnatural or Advantageous?
- Beyond weight loss: a review of the therapeutic uses of very-low carbohydrate (ketogenic) diets
- I also watched the entire interview with Dave Asprey and Dr. D’Agostino.
Based on my experience with carbohydrate manipulation, I am a pretty big fan of ketogenic dieting in certain populations. For example, populations that would benefit the most are people with hyperinsulinemia / insulin resistance, cancer, neurological diseases and anyone who wants to optimize their metabolic function. Ketones spare glucose, so when they are both present, the brain will preferably use ketone bodies as fuel source. According to Dr. D’Agostino, the emerging research demonstrates that ketone bodies are a preferred fuel source and a much more efficient metabolic fuel than glucose, that can enhance metabolic efficiency and ATP production. That is a big advantage of ketogenic diet in that you can tap into your fat reserve and mobilize fat as a fuel source more efficiently, preserving glycogen stores (D’Agostino, 2013). Other key points:
- The CNS cannot use fat as an energy source, and during starvation of glucose restriction, it sues an alternative energy source from the overproduction of acetyl coenzyme A (CoA) (Paoli, Rubini, Volek, & Grimaldi, 2013).
- The ketogenic diet and fasting mimicking diet (FMD) have different therapeutic responses that should be considered when recommending them to patients. The biggest difference between them is that the micronutrient composition varies somewhat. FMD is essentially lower in protein and higher carbohydrates. Both diets can promote ketosis.
- A fasting mimicking diet (which is essentially a low carbohydrate, low protein, low calorie diet) can suppress autoimmunity, reduce pro-inflammatory cytokines (TH1 and TH17), reduce antigen presenting cells (APC’s), induce autoimmune lymphocyte apoptosis, increase Treg cells, and increase corticosterone levels (Choi et al., 2016).
- The beauty of the FMD is the alteration of the FMD cycles and refeeding that promotes regeneration of autoimmune cells with naïve T cells. A chronic ketogenic diet may not have the same effects.
- Ketones can induce mitochondrial respiratory complex inhibitors (MRC’s), which can influence synaptic impairment. MRC’s are involved in the formation of ATP. An imbalance between ATP and ROS generation by the MRC is thought to contribute to the pathogenesis of neurodegenerative diseases (ND) (Kim, Vallejo, & Rho, 2010). They can do this through enhancing glutathione peroxidase activity, suppressing ROS generation, restoring catalase activity and ATP depletion caused by hydrogen peroxide and MRC inhibition (Kim et al., 2010).
- Ketones and the full ketogenic diet can up-regulate ATP synthesis through mechanisms that normalize MRC activity and stabilizes the mitochondrial inner membrane potential (Kim et al., 2010).
- Glutamate availability is reduced when Beta-hydroxybutyrate (BHB) replaces glucose. Glucose and BHB are both metabolized to acetyl-CoA, but the initial catabolic steps take place in cytosol via glycolysis for glucose, but BHB can enter the mitochondria directly (Lund, Risa, Sonnewald, Schousboe, & Waagepetersen, 2009).
- Neurons metabolizing BHB as an energy substrate demonstrate an altered aspartate-glutamate homeostasis. The fraction of the glutamate pool available for transmitter release was diminished when metabolizing BHB. This reduced excitatory capacity of glutamatergic neurons may play a role in the anti-convulsive effects of the ketogenic diet (Lund et al., 2009). An excess of glutamate is associated with ALS, epilepsy, and mood disorders such as anxiety, brain fog and insomnia. Elevated glutamine is highly inflammatory and can continuously overstimulate brain cells.
- Ketogenic diets can favor the conversion of glutamate to become GABA rather than aspartate. Ketosis favors using acetate for fuel, which can convert to glutamine, an essential precursor for GABA (Deans, 2011).
- The preferred fuel source for the brain is ketones, though the most available fuel source is glucose. It is actually less efficient to make ATP from glucose than it is to make ATP from ketone bodies (Deans, 2011).
- A ketogenic diet can increase the number of mitochondria in brain cells. In fact, a study in 2004 found that ketones enhanced expression of genes encoding for mitochondrial enzyme and energy metabolism in the hippocampus, which can potentially ward of disease stressors that would kill neuronal cells (Fan, 2013).
- Ketones have antioxidant effects through the ability to inhibit dangerous ROS and enhancing their breakdown by increasing the activity of glutathione peroxidase (Fan, 2013).
- Ketones can also increase poly-unsaturated fatty acids such as DHA and EPA, which can reduce oxidant production and inflammation (Fan, 2013).
- Ketones can directly inhibit the neuron’s ability to overload on glutamate, leading to decreased excitatory transmission, protecting cell death in the hippocampus by inhibiting pro-death signaling molecules (Lutas & Yellen, 2013).
- Ketones can increase GABA in the synapses as seen in some studies
- Individuals with metabolic syndrome, insulin resistance and T2D can improve insulin sensitivity in a ketogenic diet, which can reduce their risks for developing neurodegeneration (Paoli et al., 2013).
- Exogenous ketones are an effective way to elevate ketone bodies, and this effect is pronounced with MCT oil and a low carbohydrate diet (Asprey, 2013).
- For some folks, especially those that are more physically active, a carb restricted diet of 50-100g may be more appropriate than a full KD. For some people (like myself), it is helpful to have some carbohydrates in the diet.
- Some people may notice that SHBG may become elevated on ketogenic diet. This may be due to over exercising, an underlying thyroid condition, decrease in hormone receptor density and increase in receptor sensitivity. Basically, the reduction in hormones may actually not affect function, due to increase receptor sensitivity (Asprey, 2013). Also, T3 and body temperature can decline with prolonged CR.
- Prolonged ketogenic without any fiber and polyphenols can be detrimental for some people, as it was for Dave Asprey. He feels it may have initiated gut permeability and subsequent food allergies, and he felt overall ill during his 3-month experiment with a full ketogenic diet with minimal plant foods.
- In a calorie restricted state, the body can be more sensitive to drugs or agents that cross the BBB.
- A cyclical ketogenic diet may be a better option for someone who cannot adapt well to a ketogenic diet. It also may be a good approach for someone who is exercising. Essentially, they can time their carbohydrate intake around days they are exercising.
- Women may not adapt as well to ketogenic diet as most males. Common concerns include mood changes and hormone issues. It appears women may need some insulin
My clinical takeaway is that I believe the ketogenic diet or FMD can be very therapeutic in certain populations. I do find it to be a difficult diet to follow long term for some people. In the context of the microbiome and gut integrity, it may not be a good idea for most people to conduct long term. In the cases of epilepsy, cancer and neurodegeneration, the benefits may outweigh the risks. My belief still holds strong that the dietary recommendations should be individualized on a case by case circumstance. For most people who are using the dietary approach to optimize their health, I like techniques discussed by David Asprey and Dr. D-Agostino. A modified carbohydrate diet of 50-100g or a cyclical diet, combined with MCT’s and exogenous ketones, and a comprehensive exercise program that incorporates training the improve insulin sensitivity may be the best approach.
Here are the exogenous ketones I use. I like to mix the MCT with the ketones, and I put in my bulletproof coffee for a brain fueling breakfast! —>>http://bit.ly/2QgTBm5
The bundle I recommend is the MCT, keto and collagen protein powder. Collagen will help tighten the junctions in a leaky gut.
Asprey, D. (2013). Mastering Ketosis w/ Dominic D. Agostino. Retrieved (2018, November 23) from https://www.youtube.com/watch?time_continue=347&v=3vlOLw80VD0
Choi, I. Y., Piccio, L., Childress, P., Bollman, B., Ghosh, A., Brandhorst, S., . . . Longo, V. D. (2016). A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms. Cell Rep, 15(10), 2136-2146. doi:10.1016/j.celrep.2016.05.009
Deans, E. (2011). Your Brain on Ketones. Retrieved (2018, November 23) from https://www.psychologytoday.com/us/blog/evolutionary-psychiatry/201104/your-brain-ketones
Fan, S (2013). Th fat-fueled brain: unnatural or advantageous? Retrieved (2018, November 11) from https://blogs.scientificamerican.com/mind-guest-blog/the-fat-fueled-brain-unnatural-or-advantageous/
Kim, D. Y., Vallejo, J., & Rho, J. M. (2010). Ketones prevent synaptic dysfunction induced by mitochondrial respiratory complex inhibitors. J Neurochem, 114(1), 130-141. doi:10.1111/j.1471-4159.2010.06728.x
Lund, T. M., Risa, O., Sonnewald, U., Schousboe, A., & Waagepetersen, H. S. (2009). Availability of neurotransmitter glutamate is diminished when beta-hydroxybutyrate replaces glucose in cultured neurons. J Neurochem, 110(1), 80-91. doi:10.1111/j.1471-4159.2009.06115.x
Lutas, A., & Yellen, G. (2013). The ketogenic diet: metabolic influences on brain excitability and epilepsy. Trends Neurosci, 36(1), 32-40. doi:10.1016/j.tins.2012.11.005
Paoli, A., Rubini, A., Volek, J. S., & Grimaldi, K. A. (2013). Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur J Clin Nutr, 67(8), 789-796. doi:10.1038/ejcn.2013.116