Amyotrophic Lateral Sclerosis and the Keto Diet

Amyotrophic Lateral Sclerosis and the Keto Diet

Group of doctors looking at X-ray on medical conference, discussing issues

First introduced in the 1920s, the ketogenic diet gained recognition for its well-established effectiveness in managing intractable epilepsy, standing out clinically in this regard. The intricate mechanisms underlying the ketogenic diet remain complex and not fully elucidated. However, current understanding suggests potential involvement in metabolic adaptation within cellular signaling pathways, decreased neuronal excitability, and neuroprotection.

This multifaceted approach has prompted exploration into the therapeutic potential of the ketogenic diet for various neurological diseases, such as Manic Depressive Bipolar Disorder, GLUT1 Deficiency, and Amyotrophic Lateral Sclerosis (ALS). Although these conditions differ pathophysiologically, shared abnormalities in cellular energy metabolism and altered cerebral energy metabolism point to potential benefits.

Amyotrophic Lateral Sclerosis (ALS) Symptoms

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.

In the final stages of amyotrophic lateral sclerosis (ALS), the most common cause of mortality is attributed to the failure of respiratory muscles. This progression underscores the severe nature of the disease, with a significant impact on life expectancy. Statistical data reveal the grim reality faced by ALS patients: approximately 50% succumb to the condition within three years of its onset, emphasizing the rapid and aggressive nature of the disease. A further 20% manage to extend their survival to five years, while a mere 10% achieve a decade-long battle against ALS.

Survival rates beyond a decade are exceptionally rare [1], with fewer than 10% of individuals with ALS enduring for ten years. The rarity of prolonged survival is underscored by the fact that only a minuscule fraction of patients, approximately 1%, surpasses the three-decade mark. Notably, the extraordinary case of physicist Stephen Hawking stands out, defying these statistics by living with ALS for an unprecedented 55 years. His remarkable resilience and longevity in the face of ALS serve as a testament to both the variability in disease progression and the potential for exceptional cases that challenge conventional expectations.

In other words, ALS is a devastating degenerative disease with no known cure, and few treatment options exist. Treatments for ALS include glutamate blockers like riluzole, and muscle relaxers are given to reduce pain and discomfort.  Like epilepsy, the exact pathological mechanisms that underlie ALS aren’t fully understood either.  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

The genetic underpinnings of amyotrophic lateral sclerosis (ALS) are often rooted in mutations affecting the gene responsible for encoding copper/zinc superoxide dismutase (SOD1) [1]. To gain insights into the disease’s mechanisms, researchers have ingeniously developed transgenic mouse models with an overexpression of the SOD1-G93A gene, mimicking the progressive muscle weakness and respiratory failure seen in human ALS cases. These mutant SOD1-G93A mice have become instrumental in shaping the trajectory of future ALS studies and potential treatment avenues.

One notable investigation delved into the impact of a ketogenic diet on these SOD1-G93A mutant mice, revealing compelling outcomes. The mice subjected to the ketogenic diet exhibited significantly higher motor neuron counts and preserved motor function compared to their control counterparts [5]. Intriguingly, the study also uncovered impaired electron transport chain function in the mutant mice. However, the administration of the ketone body β-hydroxybutyrate successfully restored activity in neurons where electron transport chain function had either diminished or been pharmacologically blocked [5]. While these findings showcased impressive neuroprotective effects, it’s noteworthy that the study did not observe a concurrent increase in the lifespan of the mutant mice.

Building on these insights, a more recent study explored a ketogenic diet variant known as the Deanna Protocol in SOD1-G93A mutant mice. This innovative dietary approach not only delayed disease progression but also extended the life expectancy of the ALS mouse model, demonstrating improved motor function in comparison to control subjects [6]. Such encouraging results open up new possibilities, suggesting that the elevation of ketones through the ketogenic diet and its variants might hold therapeutic potential for individuals battling ALS.

These findings underscore the evolving landscape of ALS research, emphasizing the intricate interplay between genetics, diet, and neuronal function. As the scientific community delves deeper into these connections, the promise of novel therapeutic interventions for ALS patients becomes increasingly tangible.


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.

 

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