Although we often think of Huntington’s Disease as restricted to a particular part of the brain known as the basal ganglia, it actually affects most of the body. Many other brain regions, such as the cortex, thalamus, and cerebellum are also affected, as well as the skeletal muscles, and even the heart. Since this is the case, we really need to search for therapies that can improve not just cells throughout the brain, but also muscle cells throughout the body.
Glossary:
Fasting: Voluntarily not eating or drinking for a certain period of time (e.g. 12 hours or longer)
Ketogenic diet: eating a high-fat, low-carbohydrate diet
Ketosis: a state where the brain and muscle cells are getting their energy from ketones instead of glucose
Ketones: An alternative fuel source for cells (instead of glucose)
Mitochondria: The ‘batteries’ of the cell – produce energy for the cell to function
Metabolism: the chemical (metabolic) processes that take place in your body to convert food and drinks into energy
Brain and muscle cells require a ton of energy compared with most other cells, and nearly all that energy is generated by hundreds of “batteries” within each cell, called mitochondria. However, these mitochondria are quite damaged in Huntington’s Disease, which might be caused by mutant huntingtin protein. Thus, one way to treat Huntington’s may be to use a “genetic” strategy to create normal versions of the huntingtin protein, which might improve the mitochondria, leading to more energy for the brain and muscle cells. However, there could be another way we could treat Huntington’s…by using a “metabolic” strategy to improve the mitochondria directly.
Metabolism is the sum of all the chemical reactions in the brain and body, which virtually all involve mitochondria one way or another, and a metabolic strategy is just a method for altering the body’s metabolic state that aims to “restore” the health of the mitochondria. The two most common and useful metabolic strategies are probably:
(1) Fasting, which is a voluntary abstinence from food and drink for specified periods of time, minimum 12 hours.
(2) Ketogenic diets, which are high-fat, adequate-protein, low-carbohydrate diets that limit digestible carbohydrate to below 50 g daily.
Both fasting and ketogenic diets put the body into “ketosis,” which is a state where the brain and muscle cells are getting a lot of their fuel from fat-derived ketones (when fasting, the ketones come from body fat, when on a ketogenic diet, they come from dietary fat). Ketones are organic molecules that can act as an alternative fuel for these cells (instead of glucose, a simple sugar that most carbohydrates are broken down into, which is what almost everyone runs on with a “standard” diet). Compared with glucose, ketones produce more energy, fewer free radicals, and have a lot of other benefits as signalling molecules. Brain and muscle cells especially love ketones. Thus, if we could “switch” a person with Huntington’s Disease into a ketogenic state through either fasting or a ketogenic diet (or both!), maybe that could help their brain and muscle cells out with a better fuel source and, potentially, improve the health of their mitochondria - and their symptoms.
This has never been done in a human patient with Huntington’s Disease…until now, in NZ. In 2022, our group published the first case study in the world of a person with Huntington’s Disease to partake in a fasting and ketogenic diet strategy, which we called a “time-restricted ketogenic diet.” Basically, he went for 1 year on a 2-meals-per-day ketogenic diet (mainly comprised of green vegetables, meats, eggs, nuts, seeds, creams and natural oils), with no snacks, which ensured that he was in ketosis the whole time (he actually recorded it every day of the year with a blood ketone monitor, so we could be sure). He was very adherent. We measured his Huntington’s symptoms, with some of the best clinical rating scales available, to assess his movement, cognition, behaviours, , and quality of life. The measurements were at baseline (before starting the time-restricted ketogenic diet), and then at 24 weeks, and then at 48 weeks.
What happened? Well, in a nutshell, after nearly 1 year on the time-restricted ketogenic diet his motor symptoms improved by about 50%, his functional activities of daily living improved by about 30%, and his behaviours, which included apathy, disorientation, anger, and irritability (all of which were the most difficult feature of the Huntington’s for him and his wife) improved by an impressive 50-100%. His mood-related quality of life improved 25%. His cognition remained the same. He did lose 1.7 kg of weight over the year - however, he had lost 5-6 kg of weight over the preceding year while on his standard diet, so actually, he lost a lot less weight despite all that fasting! If you want to read the study in detail, click here.
It’s been about 1.5 years now since he started the time-restricted ketogenic diet, and our patient is not looking back - he remains in ketosis and wishes to stay that way. Remember, this study involved just one patient, also in the unique position of having concurrent Type 1 Diabetes, so we need to conduct larger studies with many more patients before we can be confident in saying that fasting and ketogenic diets definitely help in Huntington’s. But the results are certainly encouraging.
Despite there being quite a lot of misunderstanding out there about fasting and ketogenic diets, this case study shows that when they are used properly, perhaps they could be useful in restoring a person’s brain and muscle cell metabolism, and health in general - even in a complex disorder like Huntington’s Disease.
About The Author
Matt is a clinical and research neurologist at Waikato Hospital, Hamilton, New Zealand. His foremost passion is to explore the potential feasibility, safety, and efficacy of metabolic strategies, particularly fasting and ketogenic diets, in creating alternate metabolic states that may improve not only the symptoms, but also function and quality of life, for people with a variety of difficult neurological disorders.
