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Hope for Amyotrophic Lateral Sclerosis (ALS) with the Keto Diet

First used in the 1920s, the ketogenic diet is most known for its established efficacy in treating intractable epilepsy and is best known clinically for this role. Researchers have asked whether it could also help in other neurological diseases, including Amyotrophic Lateral Sclerosis (ALS). Here is what mouse studies have found, and why no human benefit has been shown...

Hope for Amyotrophic Lateral Sclerosis (ALS) with the Keto Diet

Hope for Amyotrophic Lateral Sclerosis (ALS) with the Keto Diet

First used in the 1920s, the ketogenic diet is most known for its established efficacy in treating intractable epilepsy and is best known clinically for this role.  Unfortunately, the mechanisms of the ketogenic diet are complex and not yet fully understood.  Though, it likely involves metabolic adaptation in cellular signaling pathways, decreased neuronal excitability, and neuroprotection.  As such, researchers have asked whether the ketogenic diet could help in other neurological diseases, including Amyotrophic Lateral Sclerosis (ALS).  Currently, the exploration into the therapeutic effects of a ketogenic diet on neurological disorders other than epilepsy is embryonic, at best.  Thus, their efficacy in treating disorders other than epilepsy in humans remains speculative.  Nevertheless, we will discuss what research on the Keto diet in ALS has found so far.  

Amyotrophic Lateral Sclerosis (ALS) Symptoms

While neurological diseases like Epilepsy, GLUT1 Deficiency, Manic Depressive Bipolar Disorder, and ALS have little in common pathophysiologically, they each feature abnormalities in cellular energy metabolism.  And, altered cerebral energy metabolism points to altered mitochondrial function.  Amyotrophic lateral sclerosis (ALS) is a rapidly progressive disease due to degeneration of motor neurons of the cerebral cortex and anterior horn of the spinal cord that is universally fatal.   It has claimed the lives of many, including physicist Stephen Hawking, heavyweight boxing champion Ezzard Mack Charles, and baseball legend Lou Gehrig who the disease is colloquially named after. Most patients with ALS present with symptoms such as cramps, weakness, and muscle atrophy of the hands or feet.  Later, weakness progresses to the forearms, shoulders, and lower limbs. Fasciculations, spasticity, hyperactive deep tendon reflexes, extensor plantar reflexes, clumsiness, stiffness, weight loss, fatigue, and difficulty controlling facial expression and tongue movements soon follow. Other symptoms include hoarseness, dysphagia, and slurred speech. Then, as swallowing becomes more difficult, patients often choke on liquids. Ultimately, death is most often caused by the failure of the respiratory muscles. 50% of patients with ALS die within three years of the onset, 20% live for five years, and 10% will have a 10-year survival rate. Survival for longer than 30 years is extremely rare [1].   Stephen Hawking lived with ALS for 55 years.  In other words, ALS is a devastating degenerative disease with no known cure, and few treatment options exist. FDA-approved treatments for ALS include the glutamate blocker Riluzole, edaravone (approved in 2017) and, for ALS associated with a SOD1 gene mutation, tofersen (accelerated approval in 2023); muscle relaxers are given to reduce pain and discomfort.   Like epilepsy, the exact pathological mechanisms that underlie ALS aren’t fully understood.   But what is known is that mechanistically, ALS likely involves oxidative damage, glutamate excitotoxicity, inflammation, and mitochondrial membrane dysfunction in nerve cells [2,3,4]. 

Amyotrophic Lateral Sclerosis (ALS) and the Keto Diet

ALS and the Ketogenic Diet

About 2% of individuals with the disease have a mutation in the gene encoding copper/zinc superoxide dismutase (SOD1) [8]. So when a transgenic mouse model of ALS was created in which the gene SOD 1-G93A was overexpressed, it led to progressive muscle weakness and death resulting from respiratory failure, similar to what occurs in humans with ALS.  Studies on the mutant SOD 1-G93A mutant mice have given a lot of direction for future ALS studies, and treatment. For example, in one study the SOD 1-G93A mutant mice were given a ketogenic diet and were found to have significantly higher motor neuron counts— and preserved motor function— compared to the control mice [5].  The authors also found that the mutant mice showed impaired electron transport chain function. However, administering the ketone body β-hydroxybutyrate restored activity in the neurons where electron transport chain function was either already decreased, or had been blocked pharmacologically [5].  While these results are indeed impressive, this study did not indicate an increase in lifespan of the mutant mice.   However, in another study in the same mouse model, mice given the main supplement ingredients of the Deanna Protocol (DP) with a standard diet or with a ketogenic diet lived 7.5% and 4.2% longer than controls, respectively, while mice fed the ketogenic diet had better motor performance [4].

The Deanna Protocol

The Deanna Protocol is a program developed by Dr. Vincent Tedone, a retired physician whose daughter, Deanna, has ALS.  The Deanna Protocol (DP) is a supplement-based metabolic therapy whose main ingredient is Arginine alpha-ketoglutarate (AAKG), and it is often combined with a ketogenic diet. The primary DP ingredients tested in mice were AAKG, GABA, Coenzyme Q10, and medium-chain triglycerides (MCT) high in caprylic triglyceride [4]. The use of the ketogenic diet in the Deanna protocol is for the purpose of utilizing ketone bodies as energy substrates, thereby bypassing the rate-limiting transport of glucose to compromised motor neurons and mitochondria.  In ALS mouse models, a ketogenic diet improved motor performance and preserved motor neurons [5], caprylic triglyceride improved motor performance without a significant survival benefit [7], and DP ingredients extended survival [4]. The Deanna Protocol has been reported anecdotally to ease symptoms in patients with ALS [4], but no clinical trial has tested the Deanna Protocol or a ketogenic diet in people with ALS, so these mouse results do not show a benefit for patients. Weight loss is a particular concern in ALS: mild obesity is associated with longer survival, and in a small randomized trial a high-carbohydrate, high-calorie tube-fed diet was safe and well tolerated, with fewer serious adverse events than the control diet [9]. Anyone with ALS considering a dietary change or supplements, including ways of raising ketones, should work with their neurologist and dietitian.

References

  1. Hulisz, D. (2018). Amyotrophic lateral sclerosis: disease state overview. Am J Manag Care, S320-S326.

  2. Vucic, S., Rothstein, J. D., & Kiernan, M. C. (2014). Advances in treating amyotrophic lateral sclerosis: insights from pathophysiological studies. Trends in Neurosciences, 37(8), 433–442. doi:10.1016/j.tins.2014.05.006

  3. Martin, L.J. (2011). Mitochondrial pathobiology in ALS. J Bioenerg Biomembr 43, 569–579.

  4. Ari, C., Poff, A. M., Held, H. E., Landon, C. S., Goldhagen, C. R., Mavromates, N., & D’Agostino, D. P. (2014). Metabolic Therapy with Deanna Protocol Supplementation Delays Disease Progression and Extends Survival in Amyotrophic Lateral Sclerosis (ALS) Mouse Model. PLoS ONE, 9(7), e103526. doi:10.1371/journal.pone.0103526

  5. Zhao, Z., Lange, D.J., Voustianiouk, A., MacGrogan, D., Ho, L., Suh, J., Humala, N., Thiyagarajan, M., Wang, J., and Pasinetti, G.M. (2006). A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis. BMC Neurosci 7, 29.

  6. D’Alessandro G, Calcagno E, Tartari S, Rizzardini M, Invernizzi RW, et al. (2011) Glutamate and glutathione interplay in a motor neuronal model of amyotrophic lateral sclerosis reveals altered energy metabolism. Neurobiology of Disease. 43(2): 346–55.

  7. Zhao W, Varghese M, Vempati P, Dzhun A, Cheng A, et al. (2012) Caprylic triglyceride as a novel therapeutic approach to effectively improve the performance and attenuate the symptoms due to the motor neuron loss in ALS disease. PLoS One. 7(11): e49191.

  8. Brown, C. A., Lally, C., Kupelian, V., & Flanders, W. D. (2021). Estimated Prevalence and Incidence of Amyotrophic Lateral Sclerosis and SOD1 and C9orf72 Genetic Variants. Neuroepidemiology, 55(5), 342–353. doi:10.1159/000516752

  9. Wills, A. M., Hubbard, J., Macklin, E. A., et al. (2014). Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet, 383(9934), 2065–2072. doi:10.1016/S0140-6736(14)60222-1

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