Diet Against Disease

Monday, January 16, 2017

“Tell me what you eat, and I will tell you what you are,” Jean Anthelme Brillat-Savarin, 1826.

What you consume not only affects the health and appearance of your body, but also the integrity of the mind.

Recently, researchers are beginning to appreciate this and have found that many neurological diseases are associated with the deterioration of energy metabolism. Metabolism involves the exchange between resource intake and energy output, and the main way to affect metabolism is through what you eat.

Diet has been used as a therapeutic against a variety of neurological diseases with varying success, but only recently are researchers beginning to explore the mechanism.

Dietary therapy in Epilepsy

The ketogenic diet, a high fat but low carbohydrate regimen, has been used since the 1920’s to treat epilepsy.

For almost 100 years, it has been known that the ketogenic diet can improve quality of life in epileptic patients by reducing seizures, defined as a sudden surge of disorganized electrical activity in the brain, but the reason why is still being explored.

In the ketogenic diet, a lack of carbohydrate reduces blood glucose levels and forces the liver to break down fat for energy, thus bypassing glycolysis, the metabolic pathway that breaks down glucose.

Breaking down fat generates ketone bodies which are then converted into energy via oxidization in the mitochondria.

Essentially you can turn on the energy-making machinery in a cell (mitochondria) by either breaking down glucose, or breaking down fat.

When you follow the ketogenic diet, or simply reduce the amount of calories you consume, you breakdown more fat.

Benefits to epileptic patients are believed to arise from two key features of these diets: reduction in glycolysis and optimization of mitochondrial function. The link between reduction in glycolysis and suppression of seizures has been shown using dietary change or direct inhibition of glycolysis in animal models.

The general theory is that calming, or normalizing, the metabolism can suppress the over-activation of neurons.

Additionally, the ketogenic diet and caloric restriction enhance mitochondrial function, such that energy is produced more efficiently and toxic byproducts are reduced.

Think about the exhaust that comes out of a car when it’s running, converting fuel into energy. In a cell, reactive oxygen species (ROS) is a type of exhaust produced by mitochondrial metabolism that can be toxic in high amounts, referred to as oxidative stress.

Other benefits of metabolic optimization that have been demonstrated including reductions in cell death and inflammatory stimulants.

Reducing glycolysis has even been shown to increase the lifespan of healthy primates. The neuroprotective nature of these effects may explain why metabolism is hypothesized to play a key role in severity of neurologic disease.

If there are so many benefits, including longer lifespan, why isn’t everyone using the ketogenic diet or restricting calories?

Well, as we’ve learned from the Atkins diet, forcing the body to subsist without carbohydrate causes more harm than good long-term. We need glycolysis too.

Much work needs to be done to parse the mechanisms, or underlying drivers, required for the benefits but not the detriments.

Diet as a disease trigger

Just as some diets can have positive effects on health and the brain, others can also add stress and even increase risk of disease.

Multiple Sclerosis (MS), is a disease where the immune system attacks the protective coating around neurons, called myelin, and has no known cure. However, various interventions can slow disease progression.

Sergio Baranzini, PhD, here at UCSF is conducting research that suggests diet can actually play a role in triggering or sustaining MS progression.

There is only a 30% genetic risk for MS, meaning that having risk-associated genes only gives you a 30% likelihood of getting the disease. Thus, MS has a large environmental risk component. Baranzini found that gut bacterial communities, or microbiota, of patients with MS differs from healthy individuals.

With collaborators from UCSD, he introduced this MS bacterial community to mice born in a sterile environment, and found that these mice had more severe disease symptoms after inducing a model of MS than mice with normal gut microbiota.

Food consumption plays a major role in the microbial composition of the digestive system, and thus makes this disease risk factor modifiable: you can remove the risk by changing behavior.

Baranzini is currently working to understand how the gut microbiome affects onset and severity of MS and plans to use this research to design an improved therapy that includes diet.

Alzheimer’s disease (AD) is yet another neuropathology where diet is considered a modifiable risk factor. A devastating age-associated dementia due to neuronal cell death, AD also has no cure and even less therapeutic options to help patient quality of life.

AD disease pathology is defined by the abnormal accumulation of proteins normally found in the human brain, mainly amyloid beta (Aβ) and tau.

The trigger of AD is still debated, but is believed to be multi-faceted and several early risk factors have been identified. Of these, metabolic conditions arising from high-fat, high-sugar, and high-cholesterol diets incur greater risk for AD later in life.

In December 2016, researchers from the Leloir Institute in Argentina published a study showing that the western diet (high in saturated sugar and fat) worsens cognition and increases Aβ pathology in a rat model of pre-symptomatic AD, relative to a standard diet. Aβ pathology is the improper disposal of extracellular Aβ protein, which builds-up and forms plaques near neurons.

In this study, western diet did not affect insulin levels, but induced metabolic syndrome, which involves a detrimental elevation of blood pressure as well as increased blood sugar levels, body fat and cholesterol.

The bioenergetics, or flow of energy production, was altered in neurons firing in the hippocampus, a sensitive brain region in AD critical in learning and memory.

Finally, the authors reported decreased expression of genes important for protecting neuronal pathways, like Sirtuin-1.

The authors conclude that diets high in fat and sugar may act as a second hit to systems already afflicted by genetic predisposition for AD.

In other words, poor diets add stress.

In November 2016 researchers from Université Laval, Canada extended this inquiry to tau neurofibrillary tangles in AD.

Tau is a protein important in building the cellular scaffolding, but an altered form found in AD can accumulate and tangle inside of neurons. Utilizing a mouse model with a human tau mutation, they found that high-fat, high-sugar, and high-cholesterol diets do not affect tau pathology.

So, we know that metabolic efficiency and the gut microbiome can affect cellular function and survival in diverse disease settings.

The question remains how this is achieved — what are the critical mechanism(s) linking diet and disease states — and furthermore, how can this understanding be exploited to treat diseases currently lacking effective pharmacologic intervention.

Tailoring diet to fight the incurable disease

Clinicians are currently using dietary interventions in careful combination with pharmacologic interventions to fight these incurable diseases. However, to date, the ketogenic diet’s ability to reduce seizures in individuals with epilepsy is the only clear successful dietary intervention..

For MS, the recommended diet is high in Vitamin D, which is found to be low in MS patients and plays critical roles in the central nervous system, from neuronal development to neuroprotection.

The combination of a balanced diet and exercise are used to make patients healthy in every controllable respect outside the disease, but a truly pathology-targeted diet has yet to be described.

The ketogenic and the mediterranean diet have been tested in AD patients with moderate success in improving cognition. AD is associated with overactive neuronal firing and epilepsy, bolstering the building argument that metabolism is critical in neuronal functioning and may be exploited as a therapeutic angle.

These studies all support the use of diet in treating neurologic disease. Certain food types or diet regimens can increase neuroprotection, whereas others can reduce neuroprotection.

The underlying principle here is that proper energy processing at the cellular level is critical for neuronal health, especially under conditions where cells are already stressed by other factors (i.e. mutations in disease risk genes).

We still have much to learn about why specific diets are associated with neuronal health. This understanding carries the potential to advance not only the treatment of currently untreatable diseases, but also to prevent their onset altogether.

As the evidence piles up demonstrating just how critical metabolic function is in the vast array of diseases, the saying ‘you are what you eat’ takes on a new and more dramatic meaning.