How Metabolic Therapies Prevent and Treat Chronic Diseases

By Dr. Mercola

Cancer has become Americans' No. 1 health concern. According to the American Cancer Society, more than 1,600 people die every day from cancer in the U.S. That's over 600,000 people each year. When you include the entire world population that number climbs tenfold to over 7.6 million. Statistics suggest half of all men and 4 out of 10 women will develop cancer during their lifetimes.

Alzheimer’s disease is another major health threat that has dramatically increased in recent years. Between 1999 and 2014, the death rate from Alzheimer’s increased by 55 percent. According to the latest statistics, Alzheimer’s claims the lives of more than half a million Americans each year, and unless there are radical changes, many experts project half of the population will eventually develop it.

These are grim statistics, but there is hope. Mounting evidence shows both of these conditions — as well as many other top killers — are metabolic diseases. This is actually good news, because that means you can prevent, treat and recover from them like other metabolic conditions, such as Type 2 diabetes and heart disease.

Ketogenic Diet Shows Tremendous Promise as Tool Against Chronic Disease

A number of experts and researchers are now convinced the answer to our burgeoning cancer and Alzheimer’s epidemics is a ketogenic diet and other metabolic support. Nutritional ketosis is the metabolic state associated with an increased production of ketones in your liver; i.e., the biological reflection of being able to burn fat, and is defined as having blood ketones in the range of 0.5 to 3.0 millimoles per liter.  

Personally, I believe metabolic therapy — starting with a ketogenic diet — is an absolutely crucial facet of dementia and cancer prevention and treatment, and hopefully some day it will be adopted as a first line of treatment by mainstream medicine. The two videos included in this article feature Dominic D’Agostino, Ph.D., assistant professor at the University of South Florida College of Medicine.

He teaches courses in molecular pharmacology and physiology, and maintains involvement in several studies researching metabolic treatments for neurological disorders such as seizures, Alzheimer’s, ALS and cancer, all of which are metabolically linked.

What Is Metabolic Therapy?

Metabolic therapy is an umbrella term that includes nutrition (primarily in the form of a ketogenic diet), dietary supplements, drugs that have a therapeutic influence on energy metabolism, fasting, hyperthermia, hyperbaric oxygen therapy and more. The focus of D’Agostino’s talk is the biological effects of nutritional ketosis and ketone supplements. The first 15 minutes or so are spent explaining the background of how he got into looking at fasting as a therapeutic aid to improve brain metabolism.

The second half of the video goes into practical applications of nutritional ketosis, and its anticancer effects. In my latest book, “Fat for Fuel,” I present a program called metabolic mitochondrial therapy (MMT), which is a form of metabolic therapy.

MMT includes not only cyclical ketosis, but also a variety of other strategies to improve your mitochondria other than diet, such as cold thermogenesis, photobiology, detox, exercise and electromagnetic field (EMF) avoidance. As noted by D’Agostino, metabolic therapies have the ability to treat a broad range of pathologies, not just cancer, making it all the more valuable from a clinical standpoint.

“In one way or another, most diseases, especially diseases of the brain — neurodegenerative diseases — are linked pathophysiologically to energy dysregulation,” D’Agostino says. “So, a metabolic therapy can often enhance brain energy metabolism in the face of these metabolic deficits.” What this means is that while you may be addressing a specific problem such as cancer, the therapy will enhance other aspects of your health as well, including your brain function. So, it’s a multiple-win situation.

Ketones Fuel Your Body and Brain During Starvation

As explained by D’Agostino, it had long been thought that the brain could only function on glucose, but studies looking at the effects of starvation showed otherwise. In fact, during starvation, such as a bout of fasting, your brain switches to using ketones  derived from dietary fats, as its primary fuel, and ketones actually enhance brain function. If you eat a regular diet, which tends to be higher in net carbs than fats, your brain will almost exclusively use glucose as its primary fuel.

D’Agostino cites a study in which overweight participants fasted for 40 days. After the first week, their ketones  skyrocketed, overtaking glucose as the primary fuel source for the body (and brain). Studies have also shown that during fasting, at least two-thirds or more of the energy your body produces is derived from ketone bodies. “So, ketones function as an alternative fuel for the brain [when] glucose is not available,” D’Agostino explains.

Now, putting your body into starvation mode through longer water fasts is not an attractive option for most people. The good news is a ketogenic diet mimics the effects of fasting in that it elevates ketones and lowers blood glucose. The key to nutritional ketosis is twofold: You need to dramatically reduce the amount of net carbohydrates you eat (total carbs minus fiber), and you need to eat a significant amount of healthy dietary fats.

This combination is what elevates your ketone level and lowers your glucose and insulin. It also mobilizes stored energy in your fat cells, which is why a ketogenic diet typically results in significant weight loss.

The Benefits of Ketone Supplementation

Ketones made by your body are called endogenous. But you can also supply your body with exogenous ketone salts or esters or from ketone precursors such as medium-chain triglyceride (MCT) oil, Coconut oil contains some MCTs, but straight MCT oil is a more concentrated source of the shorter chain fats that more easily convert to ketones.

Most commercial brands of MCT oil contain just two of the fatty acids found in coconut oil: eight-carbon (C8) and 10-carbon (C10) fats. They usually contain close to a 50/50 combination of both chain lengths.

I prefer taking straight C8 (also known as caprylic acid), as it converts to ketones far more rapidly than do C10 fats, and may be easier on your digestion. Coconut oil provides a mixture of all the medium-chain fats, including C6, C8, C10 and C12 fats, the latter of which is also known as lauric acid, which makes up over half of the fat in coconut oil. There are benefits to all of these fatty acids. However, MCT oil is more efficient at increasing ketone levels.

MCTs are processed differently from the long-chain fats in your diet. Normally, a fat taken into your body must be mixed with bile released from your gallbladder and acted on by pancreatic enzymes to break it down in your digestive system. MCTs don’t need bile or pancreatic enzymes. Once they reach your intestine, they diffuse through your intestinal membrane into your bloodstream and are transported directly to your liver, which naturally converts the oil into ketones.

Your liver then releases the ketones back into your bloodstream, where they are transported throughout your body. They can even pass your blood-brain barrier to supply your brain with energy. As noted by D’Agostino, research shows MCT oil can improve cognitive function in people with mild cognitive impairment. MCT oil will raise your ketone level even if you’re not on a ketogenic diet or fasting. The effect is not going to be as dramatic as when you’re fasting or eating a ketogenic diet, but it can mimic a mild ketogenic state.

D’Agostino also reviews the use of ketone salts and synthetic ketone esters, which he uses in his own research. Tests reveal the administration of a single dose of the synthetic ketone acetoacetate causes a rapid elevation of ketone esters within 30 minutes and is sustained for over four hours. Some of D’Agostino’s research shows nutritional ketosis can be sustained for up to 12 hours using supplemental ketones.

According to D’Agostino, “Therapeutic ketosis, up to 2.5 millimolar [per liter], is difficult to sustain, but with dietary ketone supplementation we found that it’s possible. So, we can deliver ketones within 15 to 30 minutes with administration of these synthetic ketogenic agents.” Ketone supplementation also causes a significant decrease in glucose within 30 to 60 minutes of administration. In fact, glucose is reduced to a greater degree than what can be achieved with anti-glycemic drugs like metformin.

Ketogenic Diet Often Better Than Drugs for the Treatment of Epilepsy

Epilepsy is a neurological disorder marked by abnormal electrical discharges in the brain that trigger seizures. The Epilepsy Foundation suggests epilepsy is the fourth most common neurological condition, with an estimated 65 million people worldwide affected by it.¹

Some 150,000 Americans are diagnosed with epilepsy annually, with children and older adults experiencing the highest incidence rates.² Nutritional ketosis has been shown to be a very effective treatment for many epileptics, especially children who do not respond well to the medications used.

Research shows administration of synthetic ketone ester raises seizure resistance in rats by a whopping 575 percent, “which is above and beyond any anti-seizure medication that has been tried in this model,” D’Agostino notes. He then goes on to describe and explain the anticonvulsant and neuroprotective mechanism of ketones. In summary, both a ketogenic diet and synthetic ketone supplementation alters the ratio of gamma-aminobutyric acid (GABA) and glutamate in your brain.

Glutamate is an excitatory neurotransmitter used to produce GABA, which has an inhibiting effect. The ratio between glutamate (excitatory) and GABA (inhibitory) determines the net excitability of the neurons in your brain. When you are in ketosis, the ratio of GABA to glutamate is higher than when you’re not in ketosis, which has a stabilizing and neuroprotective effect on your brain.

As explained by D’Agostino, “Not only does it deliver more energy to your brain, it prevents the brain from being in a hyperexcitable state that could trigger a seizure.”

Conditions and Diseases That Can Benefit From Ketones

D’Agostino’s research also shows that ketones suppress the generation of reactive oxygen species (ROS), damaging free radicals, by enhancing mitochondrial function. He explains, “Mitochondria are the energy organelles within the cell. They’re also the site of free radical production.

By enhancing mitochondrial efficiency — as oxygen goes through the mitochondria to produce energy — less of that oxygen becomes an oxygen free radical.” In other words, one of the neuroprotective mechanisms of ketones is their ability to reduce ROS.

This also has direct implications for cancer development. ROS are mostly generated through the coenzyme Q couple in the electron transport chain. Both glucose and fatty acids produce FADH2, which can generate ROS. In contrast, fat-derived ketone bodies produce only NADH, which increases the redox span of the coenzyme Q couple and reduces production of ROS. Hence, ketone bodies are considered a “cleaner” fuel than glucose.

Now, if you have less ROS being generated in the mitochondria, you end up with less mitochondrial damage and less DNA damage. So not only is switching the fuel you're feeding your body the key component of cancer treatment but, in my view, it's the primary way that you prevent cancer from occurring in the first place.

Ketones — whether from nutritional ketosis or use of a ketone supplement — also enhance brain energy metabolism and increase the energy reserves in your brain. These therapeutic effects can be exploited for the benefit of many different conditions and diseases, including:

Some of these syndromes, glucose transporter deficiency syndrome and Angleman’s syndrome specifically, require patients to remain on a very strict ketogenic diet to avoid seizures. D’Agostino’s research suggests supplemental ketones may be used, allowing these patients to be less strict with their diet, without forgoing the benefits of strict nutritional ketosis. In terms of wound healing, ketones have been shown to increase profusion of blood into the wounded area, thereby facilitating healing.

How Ketones Affect Cancer Cells

D’Agostino has shown that oxygen, at levels that are nontoxic to healthy cells, are toxic to cancer cells. In essence, cancer cells are more vulnerable to oxygen toxicity. His team has also demonstrated that ketones are toxic to cancer cells. When cancer cells are placed in a petri dish and fed only ketones, they simply die. Healthy cells, on the other hand, will thrive in the presence of ketones without glucose.

What this and other research tells us is that healthy cells, including brain cells, have a very high degree of metabolic flexibility and are able to thrive on either glucose or ketones (obtained through your diet from carbohydrates and healthy fats respectively). Not so with cancer cells. Defects in their metabolism due to having damaged mitochondria prevent them from metabolizing ketones. For this reason, glucose is the predominant fuel that allow cancer cells to thrive.

Research by Thomas Seyfried, Ph.D., professor of biology at Boston College and a leading expert and researcher in the field of cancer metabolism and nutritional ketosis, shows that tumor growth is tightly correlated with blood glucose levels.

When glucose and glutamine levels are low, and ketone levels are high, very little tumor growth occurs, and as glucose levels rise, tumor growth increases right along with it. In fact, the fluorodeoxyglucose PET scan is a technology that shows glucose consumption in tissue, allowing you to identify and track the aggressiveness of cancer tumors.

All Cancers Arise From Mitochondrial Dysfunction

Regardless of the cancer, cancer cells have the same metabolic phenotype — they all suffer from glucose overconsumption, which is the result of mitochondrial dysfunction. Ketones are metabolized entirely within the mitochondrial membrane, so the mitochondria must be fully functional in order to make energy from the ketones, and this is the functionality that all cancer cells lack.

Now, aside from a poor diet, your mitochondria can also be damaged from a number of chemical and environmental triggers, which is why it’s so important to eat organic whole food (to avoid pesticides and synthetic food additives) and avoid chemical exposures from household and personal care items used on a daily basis.

Also, as explained by D’Agostino, your mitochondria become increasingly damaged and dysfunctional with advancing age, and, since the mitochondria produce at least 90 percent of the energy in your cells, as your mitochondrial function starts to decline, glucose metabolism is upregulated to make up for the decline in energy production. As mitochondrial function declines, you also get destabilization of the nuclear genome, which triggers the activation of oncogenes — genes that cause cancer.

It can also inhibit tumor suppressor genes. With the activation of oncogenes, enzymatic activity of glycolysis is also increased, allowing increased generation of energy from sugar.

As noted by D’Agostino, “If all cancer arises from mitochondrial dysfunction, then replacement of damaged mitochondria with normal mitochondria should prevent cancer. In other words, mitochondrial producing sufficient respiration, i.e., energy, should suppress tumor growth regardless of the numbers and types of mutations … present in the nucleus of cancer cells.”

This, in a nutshell, is what metabolic therapies are all about, as healthy mitochondria act as an ultimate tumor suppressor. Research even shows healthy mitochondria suppress tumor growth even in the presence of an oncogene in the nucleus of a cell. As mentioned, mitochondrial function can be improved in a number of different ways, but when it comes to diet, a low-carb, high healthy-fat diet and/or fasting are the keys that unlock mitochondrial health.

According to D’Agostino, in rats, the best results were obtained from a combination of ketogenic diet, ketone supplementation and hyperbaric oxygen therapy. In summary, the rationale for using a ketogenic diet and other metabolic therapies is to address and repair the mitochondrial defects causing the condition or disease in the first place. Again, nutritional ketosis prevents and combats cancer by:

How to Assess the Health of Your Mitochondria

So, how can you assess the health of your mitochondria? There are a couple of ways of doing this. Seyfried has published a paper on the glucose ketone index (GKI) calculator³ in an open access journal, which can be accessed by anyone. You can use that calculator to assess the health and vitality of your mitochondria. The GKI calculator looks at your glucose to ketone ratio. Ketones must be measured by blood, not urine, and your glucose must be entered in millimoles, not in milligrams per deciliter (mg/dL).

If you have a glucose-to-ketone ratio of 1.0 or below, you know you have healthy mitochondria. Now, getting down to a 1.0 can be difficult. The last time I did a four-day fast, on the last day my glucose was 40 (2.2 mmol/l) and ketones were 8, giving me a ratio of 0.27, well below the 1.0 threshold.

You will likely need to do a complete water fast like I did in order to get that low. However, you don’t need to remain in that ultra-low zone for very long. On the other hand, if you have cancer, you’ll want to hit that mark as much as possible.

As explained by Seyfried in a previous interview,⁴ you can drive your blood sugar way down by doing a water fast for three to four days and then taking some exogenous ketones, such as MCT oil. Also, to prevent cancer, you don’t have to remain at this low level for longer than about five days every six months, as a general guide. If you already have cancer, you’ll want to remain at a low level longer. As explained by Seyfried:

“We’ve done some interesting linear regression analysis on survivability of mice with cancer using the GKI … There definitely is statistical relationship on how long you can keep your GKI [and] how long you can survive with a very aggressive cancer. Clearly, it’s just one biomarker system that allows individuals to help battle their own cancer.”

Helpful Resources for Implementing Metabolic Therapy

If you end up being as convinced of the merits of this theory as I am, there are several really good resources out there that you can peruse to learn more about the practical implementation of various metabolic therapies. As mentioned, “Fat for Fuel” details my complete program aimed at optimizing mitochondrial function. I also offer an online course on MMT to go along with the book.

The course consists of seven comprehensive lessons to teach you the keys to fighting chronic disease and optimizing your health and longevity. If you or someone you love has cancer, it will also augment any oncological treatment you might be undergoing. A key component that differentiates MMT from most other ketogenic eating plans is its emphasis on CYCLICAL ketosis.

Once your body starts to burn fat for fuel, you need to switch to a cyclical ketogenic diet, as long-term continuous ketosis has some serious drawbacks that may actually undermine your health and longevity. The “metabolic magic” in the mitochondria actually occurs during the refeeding phase, not during the starvation phase. Alas, you cannot get to that magic unless you first go through the starvation phase. Other helpful resources include the following:

• DietaryTherapies.com: A resource provided by Miriam Kalamian, a nutritionist who has worked with Seyfried since the very beginning, and has counseled many cancer patients about the ketogenic diet he recommends. She also collaborated with me on the creation of my MMT course
• The Charlie Foundation for Ketogenic Therapies:⁵ Recommended by D’Agostino, the Charlie Foundation is a resource for people seeking help for a diverse array of conditions, including epilepsy, migraines, depression, neurological disorders and cancer
• MetabolicOptimization.com:⁶ A blog created by D’Agostino and Travis Christofferson, author of "Tripping Over the Truth: The Return of the Metabolic Theory of Cancer Illuminates a New and Hopeful Path to a Cure.” Here you can find interviews with scientists involved in ketogenic research and much more