Neuroprotective Effects of the Ketogenic Diet (Part 2: Mechanisms and Evidence)

by Milene Brownlow, PhD

In addition to their original use as an anticonvulsant treatment (explored in Part 1 of this blog series), ketogenic diets (KDs) are increasingly viewed as a promising metabolic therapy for other neurological conditions. But first, an important question: Are KDs neuroprotective because of the reduction in glucose and insulin levels or due to the presence of ketones? Answer: Both.

On the one hand, chronic consumption of refined sugar and starches results in systemic inflammation in the body that exacerbates neuroinflammation and plays a role in blood brain barrier (BBB) disruption, impaired brain glucose utilization, mood disorders, and overall detriments to neurological health.^1-2 Thus the low-carbohydrate feature of the ketogenic diet facilitates a low intake of sugars and starches, helping to mitigate these deleterious neurological effects.

On the other hand, ketones themselves play an important, unique role in biochemical pathways associated with improved health.^3-10 From a biological standpoint, ketosis (metabolic state characterized by the accumulation of ketones in the bloodstream) is a survival mechanism that takes place during prolonged fasting, starvation or reduced carbohydrate intake. In turn, the body is required to use an alternative energy source for its metabolic requirements, such as free fatty acids. Ketones are water-soluble molecules produced in the liver from the incomplete breakdown of fatty acids and then released into the bloodstream. In addition to inducing an increase in the synthesis and utilization of ketones, dietary carbohydrate restriction results in decreased glucose utilization and, therefore, improvements in insulin sensitivity.¹¹

Let’s explore 7 ways that ketosis facilitates neuroprotection:

1. Enhanced mitochondrial function: Ketones increase mitochondrial efficiency (higher ATP yield per oxygen molecule), contributing to improved energy metabolism.³
2. Increased insulin sensitivity: Studies point to the existence of shared mechanisms between Alzheimer’s disease (AD) and type 2 diabetes.¹ In a 2013 study, researchers followed 2,067 cognitively healthy participants for 7 years and reported that higher blood glucose levels, even within the normal range, were associated with increased incidence of dementia.⁴
3. Improved brain energy metabolism: Imaging studies reveal that, despite reduced brain glucose uptake and utilization in patients with cognitive decline,⁵ the uptake of ketones across the BBB remains unchanged in these patients. Moreover, ketones enter the brain in proportion to blood levels, emphasizing their role as a valuable energy source for neurons.⁶ In fact, ketones may be the brain’s preferred fuel considering humans have survived long periods of starvation during our evolutionary history.
4. Reduced inflammation: In addition to the reduced intake of pro-inflammatory food items such as refined sugars, KDs lead to a better inflammatory profile due to direct effects of ketones on inflammation pathways.⁷
5. Suppression of oxidative stress: Beta-hydroxybutyrate (bHB) has been shown to activate antioxidant pathways and reduce generation of reactive oxygen species (as a result of increased mitochondrial efficiency).⁸
6. Epigenetic modulation: Emerging research demonstrates that ketones act as signaling molecules, coordinating cellular function via epigenetic modulation of pathways associated with longevity, energy regulation, antioxidant enzymes and inflammation.⁹
7. Modulatory effects on neurotransmitter systems: Ketones modulate neuronal excitability by reducing glutamate toxicity and increasing inhibitory (GABAergic) tone, playing a central role in the diet’s anticonvulsant properties.¹⁰

In summary, in addition to helping you achieve your metabolic goals, adopting a ketogenic lifestyle can also play a crucial role in supporting brain health. As described above, ketones are involved in several biological mechanisms associated with enhanced neuroprotection and are being considered a promising therapeutic approach in many age-related and neurological conditions. In the next part of this 3-part blog series, we will review the current scientific evidence supporting the application of KDs in specific neurological disorders.

Citations

1. Craft S. Insulin resistance syndrome and Alzheimer’s disease: age- and obesity-related effects on memory, amyloid, and inflammation. Neurobiol Aging. 2005;26S:S65-69.
2. Knüppel A et al. Sugar intake from sweet food and beverages, common mental disorder and depression: prospective findings from the Whitehall II study. Sci Reports. 2017;7:6287.
3. Veech RL. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty Acids. 2004;70:309-19.
4. Crane PK et al. Glucose levels and risk of dementia. N Engl J Med. 2013;369(6):540-48.
5. Hoyer S. Abnormalities of glucose metabolism in Alzheimer’s disease. Ann NY Acad Sci. 1991;640:53-8.
6. Cunnane SC et al. Can ketones help rescue brain fuel supply in later life? Implications for cognitive health during aging and the treatment of Alzheimer’s disease. Front Mol Neurosci. 2016;9(53).
7. Youm YH et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediate inflammatory disease. Nat Med 2015;21(3):263-9.
8. Shimazu T et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 2013;339(6116):211-4.
9. Newman JC et al. Ketone bodies as signaling molecules. Trends Endocrinol Metab. 2014;25(1): 42-52.
10. Ruan HB et al. Ketone bodies as epigenetic modifiers. Curr Opn Clin Nutr Metab Care. 2018;21(4):260-6.
11. Hammami MM. Book Review: Diabetes mellitus: A fundamental and clinical text. Ann Saudi Med. 1997;17:264.

Milene Brownlow, PhD

Dr. Milene Brownlow is a Nutrition Scientist for the Cognitive Platform at Metagenics. She has earned her PhD from the University of South Florida, studying the role of diet-induced ketosis and calorie restriction on Alzheimer’s pathology. During her postdoctoral fellowship at the Air Force Research Laboratory she investigated nutritional approaches to optimizing brain health and cognitive performance. Dr. Brownlow has extensive experience in designing, managing and executing studies in behavioral neuroscience and has authored over 12 peer-reviewed publications. In her spare time, she enjoys spending time with her husband and their daughter, exploring the beautiful Pacific Northwest.