Ketosis, Ketogenic Diets & Cancer

What is Ketosis?

Many people are confused about the idea of ketosis and ketogenic diets. Thanks to advice from uninformed medical professionals, this metabolic state is sometimes even viewed as being unhealthy. But, nothing could be further from the truth!

When you are burning sugar/glucose rather than fat for energy, your body is relying on sugar for fuel.  When burning fats for fuel, either body fat or fats consumed in your diet, you are in a state of ketosis and you are producing and burning ketones. That’s it! That is all that ketosis means. It bears repeating that the fat you use for fuel can come either from the food you consume or the body fat you carry around with you. When we breakdown fat as a fuel source it gets converted by our mitochondria into usable energy (ATP), just like blood glucose.

As a result of confusion surrounding the science of nutrition; largely as a result of a crippling level of special (often financial) interests, people often view ketosis and dietary fat as dangerous. But, fat is actually the body’s preferred source of fuel.

When people eat reduced levels of carbohydrates, (excluding some forms of fibre), they begin to burn fat for energy. As we start to burn more body fat, ketone levels rise since they are a by-product of fat metabolism. Importantly, some of those ketones are actually a preferred source of energy for specific organs. Two examples are acetoacetate and beta-hydroxybutyrate. They are the go-to energy source for heart muscle and kidney tissue. Yes, you read that correctly! Fat, (via the process of ketosis), is actually good for your heart and your kidneys. In fact, most of our cells, with a special focus on the brain, easily switch to using ketones as well as fats as an energy source.

Some people think that ketosis is “bad” largely because of confusion about two important terms. This includes many medical doctors. They are confusing two states or processes. They are diabetic “ketoacidosis (DKA)” and nutritional ketosis or “keto-adaptation”. Understanding this difference requires an explanation of what ketones are. Then it is possible to differentiate between these two processes and understand their impacts on nutrition.

A Ketone Group

A “ketone” is a chemical structure in which oxygen is double-bonded to carbon sandwiched between at least 2 other carbons. The body can produce, from fat and some amino acids, three different types of ketones.

Why do we make ketones at all if we can simply rely on blood sugar? Well, for starters the burning of sugars is a short term solution. It serves an important purpose by supplying energy for relatively short periods. It is quickly consumed. However, there have been many times in history where carbohydrate-based foods would have been non-existent as an energy source. These include ice-ages and periods of catastrophic and unpredictable weather change. If we had relied exclusively on carbohydrate and plant-based diets during these times, we would have starved to death quickly. Compounding this problem is the fact that there is no way to store glucose internally for any decent length of time. With no alternate, longer lasting, process for creating energy, life in general would never have survived. Ketones are an evolutionary solution to that need. They are a part of a process of burning fats for energy instead of burning sugars.

three ketone bodies: acetone (top), acetoacetic acid (middle), and beta-hydroxybutyric acid (bottom).

The burning of fats and ketones is a huge evolutionary advantage for air breathers. In the beginning, the simple, non DNA-storing, life of prokaryotic cells did not require oxygen because sugar/glucose based energy production was based on anaerobic processes. No oxygen was needed. In fact, there was no oxygen in the atmosphere at all. As it became available, life developed aerobic processes as second way of generating energy to live. We learned to burn both externally sourced fats and internally stored body fat for fuel.

We can’t store much more than a day’s worth of glucose at any time. If we couldn’t burn fat for energy, either externally sourced fats and or our own body fats, we would literally die within hours. Think of glucose as kindling for the anaerobic fire. It is easily burned but it only lasts for a short time. Without the aerobic ability to consume fats, either from external or internal sources, we could not have survived the famines and extreme shortages of food we have faced throughout most of our history. Fats offer a storable, easily consumable, portable, and long lasting source of energy.

The liver takes fat and the amino acids leucine and lysine and converts them into ketones. Consider the example of your brain. It functions by burning both glucose and ketones as fuel. Because of environmental pressures, the brain has developed an affinity for ketones. That is because dietary fat and stored body fat are reliable resources that do not really have an “off season”. They are always around while carbohydrates are generally seasonal. Interestingly enough, the time that most carbs are harvested in is in a single season. In North America, harvest season is in autumn. The insulin that is promoted by dietary carbohydrate intake, when combined with sufficient dietary fat, leads to stored body fat to keep us alive through the winter months when no source of carbohydrate would be around.

Traditional Hunter/Gather Society

Think of the ice age. We likely would never have had an appreciable supply of carbohydrates. Fat consumption would have been a life saver – literally! Similar conditions applied to Inuit populations until very recent times. The traditional Inuit people of the arctic were documented to have incredibly low rates of both heart disease and cancer. These examples illustrate the fact that there are no essential carbohydrate requirements for humans. There were long stretches in history where they were not available.

Now that we have a better understanding of ketosis, we can ask “What is ketoacidosis and why is it unhealthy?”

Consider what happens when diabetics cannot receive sufficient insulin. They go into a state of starvation. This generally happens in type 1 diabetics, who cannot make insulin at all. Some type 2 diabetics who can generate insulin but supplement with insulin injections can also have this as an issue when they are reducing their dosages or develop poor sensitivity to the drug. The lack of insulin in type 1 diabetics leaves them with plenty of blood sugar. But, with no insulin available, blood glucose can’t be utilized at the cellular level. In a situation like this, their body does what anyone’s else’s would. It starts consuming body fat for energy. So, though these metabolic states look somewhat similar they are not even close to having the same causes. With no insulin and the perception of starvation, there is no negative feedback to stop the breakdown of fat and the cycle continues. As the associated ketone levels (specifically, beta-hydroxybutyrate) approach the 15 to 25 mm mark, the resulting pH imbalance leads to profound metabolic derangement. The patient becomes critically ill and can even die.

Diabetic Ketoacidosis

However, if you are not a type one diabetic, your body is able to make insulin. You will not go into diabetic ketoacidosis. If it is required, you can make blood sugar internally through gluconeogenesis. If insulin is present, and assuming that the body is able to use it, the required glucose will be transported into cells. You will not repeat the cycle leading to ketoacidosis.

Ketosis is nothing to worry about in people with normal metabolisms. In fact there are some major potential benefits from being in ketosis. One of these benefits derives from the fact that cancers can only be fuelled by glucose.

Ketogenic Diets and Cancer

According to Dr. Thomas Seyfried, author of Cancer as a Metabolic Disease, “We’re not going to make major advances in the management of cancer until it becomes recognized as a metabolic disease.”

Regulating your blood-glucose leptin and insulin levels through diet, exercise, and stress management, may be one of the most critical aspects to an effective cancer recovery program. These factors are also potentially vital in preventing cancer from ever developing in the first place. Way back in 1931, the Nobel Prize was awarded to German scientist and researcher Dr. Otto Warburg for discovering that cancer cells have a deeply different energy metabolism when compared to healthy cells. He found that malignant tumours survive by using sugar for energy. As an example, recent research has determined that although cancer cells feed on both glucose and fructose, pancreatic tumour cells use fructose in particular to divide and spread throughout the body.

According to Dr. Seyfried if you restrict sugar and provide an alternate fuel, specifically fat, you can considerably reduce the rate of growth of cancer. He explains:

“When we’re dealing with glucose and [cancer] management, we know from a large number of studies that if respiration of the tumour is ineffective, in order to survive, the cells must use an alternative source of energy, which is fermentation. We know that glucose is the primary fuel for fermentation. Fermentation becomes a primary energy-generating process in the tumour cell. By targeting the fuel for that process, we then have the capability of potentially managing the disease.”

The method that Dr. Seyfried suggests is a low-carb, low to moderate protein, high-fat diet. It will effectively lower your blood sugar (glucose levels) and leave you with energy derived from ketosis. It is a measurable process that you can monitor using a blood glucose meter. This is a ketogenic diet that will also raise ketones in the body. As we have already discussed, fat is converted to ketones that your body can burn in the absence of glucose. When combined with protein restriction, these steps put your body in a metabolic state that is hostile for cancer cells.

“[A ketone] is a fat breakdown product that can replace glucose as a major fuel for many of the organs and especially our brain,” says Dr. Seyfried. Tumour cells, however, cannot use ketone bodies because their metabolism won’t allow it. So a ketogenic diet characterizes a way to focus on and marginalize tumour cells. It also allows you to dramatically lower your glucose levels, as the ketones will protect your body against any hypoglycemia that might otherwise be induced by heavy carb restriction.”

In closing, a final statement from Dr. Seyfried:

“All of the newer cells in your body will be transitioned to these effective ketones, thereby protecting them from damage from hypoglycemia. At the same time, the tumour cells are now marginalized and under tremendous metabolic stress. It’s a whole body therapy—you need to bring the whole body into this metabolic state,” he explains.

“We like to call it a new state of metabolic homeostasis: a state where ketones have reached the steady state level in your blood and glucose has reached a steady lower level in your blood… If it’s done right and implemented right, it has powerful therapeutic benefits on the majority of people who suffer from various kinds of cancers. Because all cancers have primarily the same metabolic defect.”

The Primal Origins of the Human Diet

Deep in the milky-way lies a wispy, barely detectable, gaseous interstellar cloud which contains an 8-atom sugar called glycolaldehyde. This chemical may just be a major precursor to life on planet Earth.

Sugar molecules in the gas surrounding a young Sun-like star

Glycolaldehyde can react with ribose, a 5-carbon sugar, to form RNA and DNA. DNA, or deoxyribonucleic acid, is like a biological blueprint that a living organism must follow to survive and remain functional. RNA, or ribonucleic acid, helps carry out this blueprint’s guidelines. RNA transfers the genetic code needed for the creation of building-block-proteins from information-storing-nuclei to the protein manufacturing segments of our body’s cells.

Think of DNA as a blueprint or set of instructions. RNA contains a second set of instructions for converting the blueprint into the biological house we live in. Together, they form the basis for life on this planet. Glycolaldehyde is one of the keys to the creation of both.

The same interstellar cloud that contains glycolaldehyde also contains a sweet compound called ethylene glycol. It is a close relative of sugar. This is an important actor when looking into early life on earth. In earth’s earliest days, the atmosphere contained no oxygen. Without oxygen, life was based on the production of energy using anaerobic processes that did not require the presence of oxygen. These anaerobic processes, (requiring no oxygen), allowed for the conversion of sugars as well as early forms of protein into energy. However, another kind of process was needed for fats. This requirement for a second process is a key concept in understanding how our metabolisms work at their most basic level.

The first living cells were prokaryotic in nature. Prokaryotic cells are microscopic single-celled organisms that have neither a distinct information rich nucleus with a membrane nor any other specialized oxygen-based sub-structures. Understandable since in earliest times there was no oxygen present. This means that all of the living cells on the planet were identical in their genetic structure. It also means that they primarily metabolized sugar for energy. However, there was a very important side effect to this process!

A comparison of eukaryote and prokaryote cell types

The oxygen that fills our atmosphere today was built up over millions of years as a waste-product from the prokaryotic cells’ anaerobic digestion of sugar. Once there was enough oxygen to go around, prokaryotic cells evolved into eukaryotic cells and almost all the life we see each day — including all plants and animals, are Eukaryota. Eukaryotic cells are far more complex and diverse than prokaryotes. They contain a nucleus, which stores a unique genetic blueprint. Eukaryotic cells also boast their own personal “power plants”, called mitochondria. They thrive in an oxygen rich environment. These tiny cellular substructures produce chemical energy and they hold the key to understanding the evolution of life on earth. They ushered in a whole new era. These complex eukaryotic cells eventually evolved into multicellular organisms.

But how did the eukaryotic cell itself change into more complex life forms? How did such a simple life form make the evolutionary leap from a prokaryotic cell to a more complex eukaryotic cell to plant and animal cells? The answer to these questions is a powerful statement about life on earth. Eukaryotic cells evolved through teamwork.

Endosymbiosis in a nutshell

Evidence supports the idea that eukaryotic cells are actually the product of separate prokaryotic cells that united together in a symbiotic union. In fact, the mitochondrion itself seems to be the “great-great-great-great-great-great-great-great-great grandchild” of a free-living bacterium that was engulfed by another cell. This bacterium ended up becoming a sort of perpetual houseguest. The host cell benefitted immensely from the chemical energy produced by the guest it was hosting (now called the mitochondrion). The mitochondrion in turn profited from the shielded, nutrient-rich environment surrounding it.

It is our mitochondria that produce energy by using oxygen to burn fat. Fat is an aerobic nutrient. It forms the very foundation of oxygen-based metabolisms. Fat cannot be used for anaerobic (non-oxygen-based) conversion to energy.

Essential Nutrients, Nonessential Excesses and Disease

We can discuss essential nutrients in two broad categories; macronutrients and micronutrients.

You are what you eat, and you eat what you are: fats, proteins and carbohydrates. You also must consume various other vitamins and minerals.  First we need to discuss macronutrients and then we will look at micronutrients.

What are macronutrients? Nutrients are substances essential for growth, metabolism, and other bodily functions. Macronutrients are nutrients that provide our bodies with the calories and building blocks required to make and use energy. “Macro” means large. Macronutrients are the nutrients needed in large amounts. They tend to be complex and composed of several substances. There are three macronutrients: fat, protein and carbohydrate.

What are micronutrients? Micronutrients are the vitamins, minerals, trace elements, phytochemicals, and antioxidants that are essential for good health. Micronutrients generally get a lot of attention because they can be packaged and bottled (for profit). However, when it comes to health and vitality it is ultimately macronutrients that run the show.

Nutrition has become a very confusing subject for discussion these days. What follows is basic description of the science behind what various macronutrients do and what our basic requirements are for their consumption. To be clear, this blog has strong reservations about the value of manufactured foods.  All foods that were not given to us by mother-nature directly and which require significant processing should be removed from daily life if your goal is health and longevity. This includes manufactured so-called health foods and commercially prepared factory farmed meats.

The category of macronutrients can be broken down into two subsections, essential and non-essential. Essential nutrients are nutrients that your body cannot manufacture for itself. Essential nutrients must come from external sources. Non-essential nutrients are nutrients that can be accessed internally or manufactured by combining a variety of other available nutrients.

There are essential micronutrients as well. These include the various B vitamins, vitamin C, and the fat soluble vitamins A, D, E & K. They must be accessed externally. There are also many essential minerals, including: Calcium, Chloride, Chromium, Cobalt (as part of Vitamin B12), Copper, Iodine, Iron, Magnesium, Manganese, Molybdenum, Phosphorus, Potassium, Selenium, Sodium, Zinc.

Note: There are no essential carbohydrates or sugars, all carbohydrates eventually become sugar. Why are there no essential carbs? Because we can make them via the synthesis of amino acids and glycerol obtained from fat metabolism. We can also make them through de novo synthesis (also called gluconeogenesis). Eventually, the body can adapt to a low-carbohydrate state by producing ketones (a state called ketosis) to fuel the body/brain. We can readily adjust to using ketones for fuel, except where excessive carbohydrate stores are present.  In that case, our bodies will revert to running on sugar.

We do not need carbohydrates. In fact excessive intake of carbohydrates is the cause of major diseases of affluence in the world today. These diseases include huge increases in rates of cancer and heart disease. Cutting excessive sugars and carbohydrates out of our diets will prevent a vast proportion of these diseases! We know this having observed the effects of fasting and caloric restriction.

Fasting and caloric restriction both reduce levels of insulin, which is required for the storage of blood sugar in the form of fat. Eating fat doesn’t make you “gain weight” directly. However, eating excessive amounts of sugar along with that fat is what causes us to pack on excessive and unhealthy pounds.

As well, fasting and caloric restriction reduce another growth factor called MTOR (short for mammalian target of rapamycin), which regulates cell growth and cell proliferation. MTOR is a protein sensing pathway that sets a limit on the amount of protein we can eat before it starts creating negative health effects.

Caloric Restriction

Caloric restriction, often shortened as CR, extends healthy, average, and maximum life spans. Various studies have analysed many short lived animals, including mice and rats, as well as animals with longer life spans such as primates. These studies follow a variety of species through a full lifespan in a shorter period of time than possible with humans. Studies on humans involve less severe parameters over shorter time spans for ethical reasons but their findings parallel those of animal studies. In published research, this method of eating is generally called dietary restriction, abbreviated to DR. Rodent studies conducted over the past 20 years have reliably demonstrated up to a 40% increase in maximum life span through life-long caloric restriction.

Appearance of Rhesus monkeys in old age (approximately 27.6 years). A and B show a typical control animal. C and D show an age-matched caloric restricted animal.

Unlike animal studies, in human studies of caloric restriction cannot be directly credited with the same impact on life span. We can’t directly study its effects over an entire human life span so easily and there are serious moral implications for such research. However, it has been shown provide numerous health benefits. These include lowered risks for most degenerative conditions of aging as well as improved measures of health. In recent years, more lengthy human studies of long-term and short-term calorie restriction have systematically demonstrated these benefits. Many researchers believe that the evidence to date shows the practice of caloric restriction will in fact prolong the healthy human life span. There simply isn’t enough data yet to pin down the impact on an entire life span. However, it is reasonable to deduce that the impact of caloric restriction could mean a difference of 5-10 years of life.The biological reaction to caloric restriction occurs in most species examined to date. It likely evolved early in the history of life on Earth as a tactic to boost the likelihood of surviving periodic famines. The effects of such dietary restrictions are the same whether you are a mouse that is alive for a few years or a human living for decades.

The beneficial effects of caloric restriction in laboratory animals have been known for more than 80 years, but only in the past decade has an appreciable level of funding and attention been given to this field. There are many ways that caloric restriction benefits health, including: increased insulin sensitivity and decreased oxidative stress. It even positively alters levels of the friendly bacteria in your digestive system!

How Caloric Restriction Benefits Health

There are several different ways in which caloric restriction may work. The area that seems to get the most research is related to a family of genes called Sirtuins. There are seven mammalian sirtuins that we know of (SIRT1 through SIRT7). In the last decade, these sirtuin proteins have received a lot of attention as epigenetic regulators of aging. The growing association between ageing and neurodegeneration has led researchers to investigate the role of sirtuins as potential targets for the development of novel therapies to prevent or slow down the progression of Alzheimer’s disease.

SIRT1, the most studied member of the sirtuin family, has already been shown to regulate numerous neuro-protective functions, including the antioxidant and anti-inflammatory response. It also plays a key role in the regulation of insulin, gene transcription and the production of new energy-producing mitochondria. There is a heavy research focus on SIRT1 gene expression because it can be targeted by drugs and by supplements like Resveratrol. But there is a much easier way to regulate this powerful gene expression, and it takes us back to the beginning of today’s discussion.

Simply put, SIRT1 is negatively regulated by both MTOR and Insulin. This means that excessive protein consumption and excessive carbohydrate consumption decrease the expression of our longevity genes. We are complex creatures that use oxygen to create energy. This means that we are built to burn fat, and eat fat. The sensing target for fat in our diets is a hormone called leptin. Leptin acts as an up-regulator. It encourages the expression of SIRT1 in a positive direction.

There are at least four solid reasons we are built to burn fat for fuel to create energy.

1. A sugar-burner can’t truly use stored fat for energy generation, at least not until their excess glucose runs out. When there is enough sugar/glucose available in the blood, our bodies will use it preferentially over fat. Note here that we are using the term “preferentially”. This does not mean sugar/glucose is more effective or efficient for energy production. On the contrary! Carbs have fewer calories than fat to make energy, so you are forced to eat larger volumes of them in order to have enough energy to go around.

2. When someone who is highly dependent on carbohydrates for energy goes a few extra hours without eating, they become very hungry. Think of it as essentially stoking metabolic fires with kindling (energy-light sugar) and not logs of hard-wood (energy-dense fats).  Clinical studies have even shown that the body fat of even carbohydrate-based dieters will release stored fatty acids several hours after eating and during periods of fasting. This is yet another sign that our bodies prefer fat as a fuel source, even if it is our own! Carbohydrate reliant eaters are simply replacing kindling with kindling without ever using much more efficient sources of energy.

3. A sugar-burner relies on a short-lived source of energy. Glucose will work for you if need it, but you can’t really store very much of it in your body. Even a 150 pound person who’s fairly trim with 12% body fat has 18 pounds of animal fat on hand to be converted into energy. Compare this to our ability to store sugar/glucose as muscle and liver glycogen. We are limited to around 500 grams or so. This means that sugar burners need to supply carbs from an external source, thus stopping the burning of any body fat for energy! What a bad trade-off!

4. A sugar-burner will use up glycogen fairly quickly, even during moderate exercise. That is not to say that glycogen-based exercise and efforts are not of some merit. Subject to the type of physical activity, glycogen burning can be completely necessary and expected. But, it is valuable fuel. If instead, you’re able to stay in an oxygen-based fat-burning mode for as long as possible you are able to save glycogen for anaerobic “all out” efforts. Glycogen stores are literally life-saving rocket fuel for running like Hell from dangerous wild animals. Sugar-adapted people are wasting their glycogen stores on efforts that fat should be able to power.

 Fat as a Source of Fuel: Our Evolutionary History

It is our birthright to be strong and lean.

Looking at metabolism through the lens of evolution, we can see that fat and protein were the dominant macronutrients, (when we were lucky enough to have any food at all). Over our two and a half million years of adaptation we have sometimes not had regular access to food, especially in the form of glucose promoting carbohydrates. This would have caused our ancestors to develop effective ways to tap their own stored body fat for energy instead of relying on a steady supply of carbohydrate. Normally, our activities would not have required the level of energy that sugar can provide. After all, we were usually not in full blown flight mode (hopefully!).  As a result, we have a very low levels of glycogen (for emergencies) compared to available fat rations in our bodies. Clearly it was primarily the fats and ketones, with small amounts of glucose generated internally through gluconeogenesis, that supplied us with appropriate levels of energy for healthy living. We would have had an occasional all-out-burst of required anearobic energy (because we could not consume oxygen quickly enough) running after, or away from an animal, but these moments would have been rare in a 24 hour day.

In Conclusion

Eating is our birthright. The importance of sugars, proteins, and fat in our diets dates back to the earliest days on the planet.  At a molecular level, it an important part of a three cornered connection to the stars involving anaerobic (based on sugars) as well as aerobic (based on fats) energy production. We are literally built to eat properly and when we follow our natural genetic preferences we are paid back with the fruits of vitality and longevity.

An important revelation here is that, despite recent arguments to the contrary, high fat diets have been shown, in human subjects, to actually increase the number of mitochondria available for energy production. This leads us to an interesting point to be covered in an upcoming post on this blog, the influence of ketogenic diets and the progression of cancer.