The Triple Helix @ UChicago

Fall 2018

"From Cheetos to Keto: A case for the disease-modifying diet gaining traction around the world" by Jack Osborn


The ketogenic diet has been touted for years as a quick solution for weight loss. The enduring effects of the diet have been studied as part of treatment for patients with epilepsy and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and dementia. While the diet primarily provided treatment for epilepsy during the 1920s, efforts have increasingly shifted towards treatment of neurodegenerative disease within the last 15 years. Results have indicated the diet may confer neuroprotective effects, suggesting its potential as a long-term disease modifier.

The diet utilizes fatty acids through consumption of fats, resulting in higher levels of ketone bodies including acetone, beta-hydroxybutyrate, and acetoacetate, most of which are produced by the liver. Rather than using glucose as a main source of fuel, which results in high levels of circulating free radicals in the blood, the use of ketone bodies has been identified as a “principal source of energy during early postnatal development.”[1] When subjected to the mechanism by which fatty acids are oxidized, ketone bodies present a cleaner, more efficient fuel source that not only do not produce free radicals, but also do not become an energy burden on the body. Studies suggest that intake of medium-chain triglycerides by patients suffering from Alzheimer’s disease ameliorates memory impairment by producing higher levels of beta-hydroxybutyrate. In one double-blind, placebo-controlled study consisting of two study visits on separate days, 20 subjects with Alzheimer’s Disease consumed either medium-chain triglycerides or placebo. Significantly increased beta-hydroxybutyrate levels (an average of 7.7-fold increase) were detected in the non-placebo patients (P = 0.067) during cognitive examinations occurring 90 min after consumption.[2] The study concluded that increased levels of beta-hydroxybutyrate in the subjects were associated with higher changes in paragraph recall scores. 


Fig 1. Relationship between beta-hydroxybutyrate levels at the time of cognitive testing and the change in paragraph recall following MCT treatment; r = 0.50, P = 0.02.

This conclusion is bolstered by the fact that upon reversal of this administration, patients who were provided a carbohydrate-rich meal experienced an opposing effect, one of worsening cognitive performance and behavior in Alzheimer’s patients.[3,4]

Consumption of a high-fat diet results in a surge of blood triglycerides; considering the brain is composed of 60% fat, accordingly, studies have consistently shown that the ketogenic diet increases cognitive function in patients suffering from neurodegenerative disease. Furthermore, the span of effects of the ketogenic diet is not limited to cognitive function. In a 2005 rodent study conducted by Van Der Auwera that investigated the effect of the ketogenic diet on Alzheimer’s disease, researchers discovered that the diet could potentially have a protective effect against amyloid-beta (Aβ), a protein associated with amyloid plaques present in Alzheimer’s patients’ brains. The transgenic mice models of Alzheimer’s disease used in the study expressed a protein, which is also found in humans, containing the London mutation of the human amyloid precursor gene. The researchers noted that the mice exhibited a “significant level of soluble Aβ in the brain as early as 3 months of age” and showed “extensive plaque deposition by 12-14 months.”[1] Thus, the results of ketone administration to rodents with the mutation suggest that exposure to the diet has not only a plaque-reducing effect, but also an epigenetic effect. However, there is a lack of investigation of the effects of the diet on a mutated β-amyloid precursor gene in human subjects. Determining whether or not the effect on Alzheimer’s disease with respect to the amyloid gene is extended to humans thus requires further study. By virtue, lack of human studies fails to bolster advocacy of the diet to treat diseases such as Alzheimer’s disease. 

Conferred benefits of the diet with respect to treatment of Parkinson’s disease are still not well-established. Caloric restriction, which may prompt ketosis, has been shown to cause “resistance to MPTP-induced loss of dopamine neurons and less severe motor deficits than animals on the normal diet” in rhesus monkeys.[1] In multiple animal studies, Parkinson’s disease has been associated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin, which causes the degeneration of mesencephalic dopamine neurons in the brain. The degeneration of said dopaminergic neurons is reduced by the administration of β-hydroxybutyrate in mice. It has been found that β-hydroxybutyrate provides protection against MPTP degeneration of neurons, providing protection by virtue of greater oxidative phosphorylation efficiency, and therefore higher ATP production.[5] However, the effects of administration of ketone bodies in the form of β-hydroxybutyrate infusion alone are yet to be determined.

Because it is well-understood that inflammation is the source of diseases including Alzheimer’s, dementia, and Parkinson’s, ketosis may play a vital role in activating anti-inflammatory signal transduction mechanisms throughout the body. Cullingford notes that “it has been shown that fatty acids activate peroxisome proliferator-activated receptor α, which may, in turn, have inhibitory effects on the proinflammatory transcription factors nuclear factor κB and activation protein – 1.”[6] To further the point that ketosis improves mitochondrial efficiency, and therefore presents less of an energy cost to cells, Sullivan notes that the diet boosts the manufacturing of mitochondrial uncoupling proteins called UCPs by lowering the mitochondrial membrane potential, thereby reducing the reactive oxygen species (ROS) in the cell.[7] Furthermore, a study analyzing ATP inhibition of cytochrome c oxidase in rat mitochondria found that an absence of ADP causes membrane potential to increase, and as a result, hinders the activity of proton pump complexes I, III, and IV. The delivery of uncoupling proteins, specifically uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP), extinguishes the membrane potential and massively prompts the uptake of oxygen, thereby increasing mitochondrial ATP synthesis.[8] 

Furthermore, the effects of the diet on the metabolism of glucose in humans over a long period of time remains unclear. In a study consisting of 10-week-old male mice that consumed either a ketogenic diet or a regular mice diet, glucose tolerance was measured at multiple points in time over the course of 22 weeks, and insulin tolerance was determined following 22 weeks of the diet. The results show that after 20 weeks of being fed a ketogenic diet, insulin secretion due to glucose was reduced in the experimental group, and following week 12 of administration of the diet, the mice became glucose intolerant, suggesting that the employment of the diet long-term prompts glucose intolerance in mice.[8] Although the diet is suggested to improve insulin sensitivity and glucose tolerance, these results produced in an animal study suggest otherwise.


Fig 2. Glucose tolerance in control and KD-fed mice. Blood glucose concentrations during the glucose tolerance test after 1 (A), 5 (B), 12 (C), and 20 wk (D) of diet (n = 5–10 mice). Insulin concentrations during the glucose tolerance test after 1 (E), 5 (F), 12 (G), and 20 (H) wk of diet (n = 3–10 mice). Area under the curve (AUC) 0–15 min insulin concentrations during the glucose tolerance test after 1 (I), 5 (J), 12 (K), and 20 (L) wk of diet (n = 4–10 mice). *P < 0.05, **P < 0.01, and ***P < 0.001 vs. control.

In addition, the study claims that the diet induces hepatic steatosis, also commonly referred to as “fatty liver disease.” Multiple markers associated with the disease in humans were analyzed in the experimental group of mice. After 22 weeks, the concentration of triglyceride present in the liver increased substantially in the ketogenic diet-fed mice. The study determined that triglyceride levels present in the liver were a defining criterion of the disease. Results show more than double the amount of liver triglycerides in the experimental mice than in the control group: experimental (379 ± 41 nmol/ mg protein) vs control (159 ± 19 nmol/mg protein).


Table 1. Plasma markers of the metabolic syndrome in control mice and mice fed a ketogenic diet for 22 weeks.

While the extent to which ketone bodies affect the body is not well-understood, it is widely accepted that by improving energy production in brain mitochondria, ketone bodies can provide anti-inflammatory and antioxidant benefits to the cell. Further investigation is required to determine whether a longitudinal or a short-term study is most efficient and whether or not particular ketone bodies (in particular, their precursors) should be administered. Whether or not ketone bodies should be administered at a particular stage of life when brains are still developing, forming neural connections, and are thus very receptive to change, such as adolescence, is yet to be determined. The potential for the diet to aid in time-efficient weight loss is substantial, however the diet should not be accepted as a panacea as further research is yet to performed.


[1] Ellenbroek, Johanne H., Laura van Dijck, Hendrica A. Töns, Ton J. Rabelink, Françoise Carlotti, Bart E. P. B. Ballieux, and Eelco J. P. de Koning. 2014. "Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice." American Journal of Physiology – Endocrinology and Metabolism. 306 (5): E552-E558. doi:10.1152/ajpen- do.00453.2013.

[1] Gasior, Maciej, Michael A. Rogawski, and Adam L. Hartman. 2006. "Neuroprotective and disease-modifying effects of the ketogenic diet." Behavioural Pharmacology. 17 (5-6): 431-439. doi:10.1097/00008877-200609000-00009.

 [2] Reger, Mark A., Samuel T. Henderson, Cathy Hale, Brenna Cholerton, Laura D. Baker, G.S. Watson, Karen Hyde, Darla Chapman, and Suzanne Craft. 2004. "Effects of β-hydroxybutyrate on cognition in memory-impaired adults." Neurobiology of Aging. 25 (3): 311-314. doi: 10.1016/s0197-4580(03)00087-3.

[3] Young K.W., Greenwood C.E., van R.R., Binns M.A. “A randomized, crossover trial of high-carbohydrate foods in nursing home residents with Alzheimer’s disease: associations among intervention response, body mass index, and behavioral and cognitive function.” J Gerontol A Biol Sci Med Sci. 2005;60:1039–1045.

[4] Henderson S.T. “High carbohydrate diets and Alzheimer’s disease.” Med Hypotheses. 2004; 62:689–700.

[5] Tieu K., Perier C., Caspersen C., Teismann P., Wu D.C., Yan S.D., et al. 2003. “D-β-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease.” J Clin Invest. 112:892–901.

[6] Cullingford T.E. 2004. “The ketogenic diet; fatty acids, fatty acid-activated receptors and neurological disorders.” Prostaglandins Leukot Essent Fatty Acids. 70:253–264.

[7] Sullivan P.G., Rippy N.A., Dorenbos K., Concepcion R.C., Agarwal A.K., Rho J.M. 2004. “The ketogenic diet increases mitochondrial uncoupling protein levels and activity.” Ann Neurol. 55:576–580.

[8] Ramzan R., Staniek K., Kadenbach B., Vogt S. 2010. “Mitochondrial respiration and membrane potential are regulated by the allosteric ATP‐inhibition of cytochrome c oxidase.” Biochim Biophys Acta 1797: 1672–80.

[9] Ellenbroek J.H., van Dijck L., Tons H.A., Rabelink T.J., Carlotti F., et al. 2014. “Long-term ketogenic diet causes glucose intolerance and reduced beta- and alpha-cell mass but no weight loss in mice.” Am J Physiol Endocrinol Metab 306: E552–558. 10.1152/ajpendo.00453.2013 

[10] Kadenbach, Bernhard, Rabia Ramzan, Katrin Staniek, and Sebastian Vogt. 2010. "Mitochondrial respiration and membrane potential are regulated by the allosteric ATP-inhibition of cytochrome c oxidase." Biochimica Et Biophysica Acta (BBA) – Bioenergetics. 1797: 92. doi: 10.1016/j.bbabio.2010.04.277.

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