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mitochondria
*** A cell can produce energy in two ways: aerobically, in the mitochondria, or anaerobically, in the cytoplasm, the latter of which generates lactic acid — a toxic byproduct. Warburg discovered that in the presence of oxygen, cancer cells overproduce lactic acid. This is known as The Warburg Effect.
Warburg concluded that the prime cause of cancer was the reversion of energy production from aerobic energy generation to a more primitive form of energy production, anaerobic fermentation. ***
Date: 5/30/2016 11:35:47 AM ( 8 y ) ... viewed 769 times
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By Dr. Mercola
In 1931, Dr. Otto Warburg won the Nobel Prize Physiology or Medicine for his discovery that cancer cells have a fundamentally different energy metabolism compared to healthy cells.
Most experts consider him to be the greatest biochemist of the 20th century. His lab staff also included Hans Krebs, Ph. D., after whom the Krebs cycle1 was named.
The Krebs cycle refers to the oxidative reduction pathways that occur in the mitochondria. So just how does the metabolic inflexibility of cancer cells differ from healthy cells?
A cell can produce energy in two ways: aerobically, in the mitochondria, or anaerobically, in the cytoplasm, the latter of which generates lactic acid — a toxic byproduct. Warburg discovered that in the presence of oxygen, cancer cells overproduce lactic acid. This is known as The Warburg Effect.
Mitochondrial energy production is far more efficient, capable of generating 18 times more energy in the form of adenosine triphosphate (ATP) than anaerobic energy generation.
Warburg concluded that the prime cause of cancer was the reversion of energy production from aerobic energy generation to a more primitive form of energy production, anaerobic fermentation.
To reverse cancer, he believed you had to disrupt the energy production cycle that is feeding the tumor, and that by reverting back to aerobic energy metabolism you could effectively "starve" it into remission.
Although he was never able to conclusively prove it, he maintained this view until his death in 1970. One of his goals in life was to discover the cure for cancer. Sadly, as so typically happens in science, his theories were never accepted by conventional science despite his academic pedigree — until now.
The New York Times2 recently published a long, detailed article about the history of modern cancer research, including Warburg's theories on cancer, which are now becoming more widely accepted.
Sugar Feeds Cancer
Another simpler way of explaining Warburg's discovery is that cancer cells are primarily fueled by the burning of sugar anaerobically. Without sugar, most cancer cells simply lack the metabolic flexibility to survive. As noted in the New York Times (NYT) featured article:
"[T]he Warburg effect is estimated to occur in up to 80 percent of cancers. [A] positron emission tomography (PET) scan, which has emerged as an important tool in the staging and diagnosis of cancer works simply by revealing the places in the body where cells are consuming extra glucose.
In many cases, the more glucose a tumor consumes, the worse a patient's prognosis."
Unfortunately, Warburg's theories quickly vanished into obscurity once scientists turned their attention toward genetics. Molecular biologists James Watson, Ph. D., and Francis Crick, Ph. D., discovered DNA in 1953 and from that point on, cancer research began to primarily focus on genetics.
The gene hypothesis gained even more momentum once Dr. Harold Varmus and Dr. Michael Bishop won the Nobel Prize in 1976 for finding viral oncogenes within the DNA of cancer cells.
At that point, the attention fell squarely on genetic mutations, and the theory that cancer cells are simply distorted versions of normal cells began to take hold.
The Warburg Revival
It would take another 30 years before the next major revision to the reigning cancer hypothesis. In 2006, the Cancer Genome Atlas project, designed to identify all the mutations thought to be causative for cancer, came to an astonishing conclusion — the genetic mutations are actually far more random than previously suspected.
In fact, they're so random it's virtually impossible to pin down the genetic origin of cancer. Some cancerous tumors even have NO mutations at all. Rather than offering the conclusive evidence needed to put an end to cancer, the Cancer Genome Atlas project revealed something was clearly missing from the equation.
With time, researchers began pondering whether cancer development might in fact hinge on Warburg's theory on energy metabolism. In recent years, scientists have come to realize that it's not the genetic defects that cause cancer.
Rather mitochondrial damage happens first, which then triggers nuclear genetic mutations. As noted by The New York Times:
"There are typically many mutations in a single cancer. But there are a limited number of ways that the body can produce energy and support rapid growth. Cancer cells rely on these fuels in a way that healthy cells don't.
The hope of scientists at the forefront of the Warburg revival is that they will be able to slow — or even stop — tumors by disrupting one or more of the many chemical reactions a cell uses to proliferate, and, in the process, starve cancer cells of the nutrients they desperately need to grow.
Even James Watson, Ph.D. one of the fathers of molecular biology, is convinced that targeting metabolism is a more promising avenue in current cancer research than gene-centered approaches ...
'I never thought ... I'd ever have to learn the Krebs cycle,' he said, referring to the reactions ... by which a cell powers itself. 'Now I realize I have to.'"
Cancer-Causing Genes Regulate Cells' Nutrient Consumption
The genetic component has not completely fallen by the wayside though. Scientists have discovered that a number of genes known to promote cancer by influencing cell division — including a gene called AKT — also regulate cells' consumption of nutrients. So certain genes do appear to play a role in cancer cells' overconsumption of sugar.
"Dr. Craig Thompson, the president and chief executive of the Memorial Sloan Kettering Cancer Center, has been among the most outspoken proponents of this renewed focus on metabolism ...
His research showed that cells need to receive instructions from other cells to eat, just as they require instructions from other cells to divide.
Thompson hypothesized that if he could identify the mutations that lead a cell to eat more glucose than it should, it would go a long way toward explaining how the Warburg effect and cancer begin," The New York Times writes.
"The protein created by AKT is part of a chain of signaling proteins that is mutated in up to 80 percent of all cancers. Thompson says that once these proteins go into overdrive, a cell no longer worries about signals from other cells to eat; it instead stuffs itself with glucose.
Thompson discovered he could induce the 'full Warburg effect' simply by placing an activated AKT protein into a normal cell. When that happens, Thompson says, the cells begin to do what every single-celled organism will do in the presence of food: eat as much as it can and make as many copies of itself as possible."
Whereas healthy cells have a feedback mechanism that makes it conserve resources when there's a lack of food, cancer cells do not have this mechanism, and feed continuously.
As noted by Dr. Chi Van Dang, director of the Abramson Cancer Center at the University of Pennsylvania, cancer cells are "addicted to nutrients," and "when they can't consume enough, they begin to die. The addiction to nutrients explains why changes to metabolic pathways are so common and tend to arise first as a cell progresses toward cancer."
Novel Treatment Offers Hope for Cancer Patients
A brilliant Korean biochemist by the name of Young Hee Ko, Ph.D., who was working in the early 2000s with Peter Pedersen, a professor of biological chemistry and oncology at Johns Hopkins, made a remarkable discovery that offers a great deal of hope for cancer patients. Today Ko is the CEO of KODiscovery at the University of Maryland BioPark, where she continues her work in the field of cellular metabolism in cancer and neuro-degenerative disease.
I believe she has the answer to a large number of intractable metastatic cancers, and predict she'll eventually receive a Nobel Prize for her work. I will actually be presenting with Ko at the Conquering Cancer Conference in Orlando on September 23 and 24 of this year..
What the two of them noticed was that when cancer cells overproduce lactic acid, they have to produce more pores, called monocarboxylic acid transfer phosphates, to let lactic acid out, or else the cancer cell will die from the inside out. As mentioned, lactic acid is a very toxic substance. Pondering how to best exploit this functional difference between normal cells and cancer cells, Ko remembered a compound called 3-bromopyruvate (3BP), which she'd worked with while getting her Ph.D.
This molecule looks very similar to lactic acid, but it's highly reactive. She thought 3BP might be able to slip into the pore that's allowing the lactic acid to be expelled from the cancer cell, thereby preventing the lactic acid from spilling out. Her hunch was correct. In over 100 lab tests, 3BP blew away all of the chemotherapy drugs she used for comparison. In a nutshell, 3BP "melts" tumors away by preventing the lactic acid from leaking out of the cancer cell, thereby killing it from the inside.
Old Diabetes Drug May Find New Use in War on Cancer
Interestingly, metformin, a drug that decreases serum glucose in diabetics, has also been shown to have anti-cancer effects — another nod at Warburg's theory that cancer cannot thrive in a low-glucose environment. As noted in the featured article:
"In the years ahead, [metformin is] likely to be used to treat — or at least to prevent — some cancers. Because metformin can influence a number of metabolic pathways, the precise mechanism by which it achieves its anticancer effects remains a source of debate. But the results of numerous epidemiological studies have been striking.
Diabetics taking metformin seem to be significantly less likely to develop cancer than diabetics who don't — and significantly less likely to die from the disease when they do.
Near the end of his life, Warburg grew obsessed with his diet. He believed that most cancer was preventable and thought that chemicals added to food and used in agriculture could cause tumors by interfering with respiration. He stopped eating bread unless it was baked in his own home. He would drink milk only if it came from a special herd of cows ...
Warburg's personal diet is unlikely to become a path to prevention. But the Warburg revival has allowed researchers to develop a hypothesis for how the diets that are linked to our obesity and diabetes epidemics — specifically, sugar-heavy diets that can result in permanently elevated levels of the hormone insulin — may also be driving cells to the Warburg effect and cancer."
Although metformin likely has some benefit in improving mitochondrial dysfunction, I believe that there are far better options, as metformin has been associated with vitamin B12 deficiency. Berberine is a natural plant alkaloid that is far safer and works similarly. However, both will be miserable failures if one does not restrict protein to less than 1 gram/kilogram of lean body mass and net carbs to less than 40 grams per day.
From my perspective, ignoring diet as a prevention tool is foolhardy at best. Like Warburg, I'm convinced that most cancers are preventable through proper diet and nutrition, and besides optimizing your nutrient ratios, avoiding toxic exposures is another important factor. This is one reason why I recommend eating organic foods, especially grass-fed or pastured meats and animal products, whenever possible.
The Importance of Diet for Successful Cancer Treatment
The foundational aspect that must be addressed is the metabolic mitochondrial defect, and this involves radically reducing the non-fiber carbohydrates in your diet and increasing high-quality fats. You may need up to 85 percent of your dietary calories from healthy fats, along with a moderate amount of high-quality protein, as excessive protein can also trigger cancer growth.
That's really the solution. If you don't do that, other treatments, including 3BP, probably will not work. (However, I believe that if you're in nutritional ketosis and then add 3BP, you may be able to reverse just about any cancer. That's my current impression. It may be flawed, and I will revise it as necessary, but everything I've seen so far points in that direction.)
It's important to remember that glucose is an inherently "dirty" fuel as it generates far more reactive oxygen species (ROS) than burning fat. But to burn fat, your cells must be healthy and normal. Cancer cells lack the metabolic flexibility to burn fat and this why a healthy high-fat diet appears to be such an effective anti-cancer strategy.
When you switch from burning glucose as your primary fuel to burning fat for fuel, cancer cells really have to struggle to stay alive, as most of their mitochondria are dysfunctional and can't use oxygen to burn fuel. At the same time, healthy cells are given an ideal and preferred fuel, which lowers oxidative damage and optimizes mitochondrial function. The sum effect is that healthy cells begin to thrive while cancer cells are "starved" into oblivion.
For optimal health, you need sufficient amounts of carbohydrates, fats, and protein. However, ever since the advent of processed foods and industrial farming, making healthy selections has become a more complex affair. There are healthy carbs and unhealthy ones. Ditto for fats. There are also important considerations when it comes to protein, as excess protein also contributes to poor health. From my review of the molecular biology required to optimize mitochondrial function, it is best to seek to have about:
•75 to 85 percent of your total calories as healthy fat
•8 to 15 percent as carbs, with twice as many fiber carbs as non-fiber (net) carbs
•7 to 10 percent of your calories as protein (high-quality grass-fed or pastured meats and animal products)
Dietary Considerations: Fats
Healthy fats3 represent about 75 to 85 percent of your daily calories. The key here is HEALTHY fats as the vast majority of fats people eat are unhealthy. Avoid all processed and bottled oil with the exception of third party certified olive oils, as 80 percent are adulterated with vegetable oils.
Ideally you should have more monosaturated fats than saturated fats. Limit polyunsaturated fat (PUFA) to less than 10 percent. At higher levels, you will increase the PUFA concentration in the inner mitochondrial membrane, which makes it far more susceptible to oxidative damage from the reactive oxygen species generated there.
Lastly, do not exceed 5 percent of your calories as omega-6 fats. Combined, your omega 6/omega 3 fats should not exceed 10 percent, and the omega 6:3 ratio should be below 2. Sources of healthy fats include:
Olives and olive oil
Coconuts and coconut oil
Butter made from raw grass-fed organic milk, and cacao butter
Raw nuts, such as, macadamia and pecans, and seeds like black sesame, cumin, pumpkin, and hemp seeds
Organic pastured egg yolks
Avocados
Grass-fed meats
Lard, tallow and ghee
Animal-based omega-3 fat such as krill oil
Dietary Considerations: Carbs
When it comes to carbohydrates, there are fiber-rich low net carbs, (mainly vegetables) and non-fiber carbs (think sugar and processed grains). Ideally, you want twice as many fiber carbs as non-fiber carbs (net carbs). So if your total carbs is 10 percent of your daily calories, at least half of that should be fiber.
Fiber is not digested and broken down into sugar, which means it will not adversely impact your insulin, leptin and mTOR levels. Fiber also has a number of other health benefits, including weight management and a lower risk for certain cancers.4 As noted in the featured NYT article, your insulin level plays a very important role in cancer.
"The insulin hypothesis can be traced to the research of Dr. Lewis Cantley. In the 1980s, Cantley discovered how insulin, which is released by the pancreas and tells cells to take up glucose, influences what happens inside a cell.
Cantley now refers to insulin and a closely related hormone, IGF-1 (insulin-like growth factor 1), as 'the champion' activators of metabolic proteins linked to cancer. He's beginning to see evidence, he says, that in some cases, 'it really is insulin itself that's getting the tumor started.'
One way to think about the Warburg effect, says Cantley, is as the insulin, or IGF-1, signaling pathway 'gone awry — it's cells behaving as though insulin were telling it to take up glucose all the time and to grow.' Cantley, who avoids eating sugar as much as he can ... says that the effects of a sugary diet on colorectal, breast and other cancer models 'looks very impressive' and 'rather scary.'"
The most important number to keep track of is your net carbs, which you'll want to keep as low as possible. Net carbs are calculated by taking the total number of carbohydrates in grams and subtracting the amount of fiber contained in the food. The resulting number is your net carbs. For optimal health and disease prevention, I recommend keeping your net carbs below 40 or 50 grams per day.
The only way you'll know how many fiber and net carbs you eat is to keep a diary of what you eat. Excellent sources of high-fiber carbs that you can eat plenty of include:
Chia seeds
Berries
Raw nuts
Cauliflowers
Root vegetables and tubers, such as onions and sweet potatoes
Green beans
Peas
Vegetables, such as broccoli and Brussel sprouts
Psyllium seed husks
Dietary Considerations: Protein
Last but not least, there's an upper limit to how much protein your body can actually use, and eating more than your body requires for repair and growth will simply add fuel to disease processes. An ideal protein intake is likely around one-half gram of protein per pound of lean body mass. For most people this equates to about 40 to 60 grams a day, but many Americans typically consume three to five times that amount, which — just like excess sugar — can raise your risk of cancer.
Substantial amounts of protein can be found in meat, fish, eggs, dairy products, legumes, nuts, and seeds. Some vegetables, such as broccoli, also contain generous amounts of protein. To estimate your protein requirements, first determine your lean body mass. Subtract your percent body fat from 100. For example, if you have 20 percent body fat, then you have 80 percent lean body mass. Just multiply that percentage (in this case, 0.8) by your current weight to get your lean body mass in pounds or kilos.
Next, jot down everything you eat for a few days, and calculate the amount of daily protein you've consumed from all sources. Again, you're aiming for one-half gram of protein per pound of lean body mass. If you're currently averaging a lot more than what is optimal, adjust downward accordingly. The chart below will give you a general idea of the protein content of various foods.
Red meat, pork, poultry, and seafood average 6 to 9 grams of protein per ounce.
An ideal amount for most people would be a 3-ounce serving of meat or seafood (not 9- or 12-ounce steaks!), which will provide about 18 to 27 grams of protein
Eggs contain about 6 to 8 grams of protein per egg. So an omelet made from two eggs would give you about 12 to 16 grams of protein
If you add cheese, you need to calculate that protein in as well (check the label of your cheese)
Seeds and nuts contain on average 4 to 8 grams of protein per quarter cup
Cooked beans average about 7 to 8 grams per half cup
Cooked grains average 5 to 7 grams per cup
Most vegetables contain about 1 to 2 grams of protein per ounce
Optimizing Mitochondrial Function Is Key for Cancer Prevention and Treatment
We're now starting to realize that mitochondrial dysfunction is at the core of virtually all diseases — cancer especially — and your lifestyle has everything to do with this situation. Hence strategies that support and optimize mitochondrial function, such as nutritional ketosis (achieved by a high-fat, low-net carb diet), intermittent fasting and high-intensity exercise are all part of the solution.
One of the basic reasons why a high-fat, low-net carb diet works so well is because it drives your inflammation down to almost nothing. And when inflammation disappears, your body can heal. It will also take the proverbial foot off the gas pedal of aging. Sadly, my guess is that over 99 percent of the population is not receiving the benefits of this approach simply because they either haven't heard of it or don't understand it.
This is why my next book will focus on mitochondrial optimization. I firmly believe it's a major key to tackling not only the cancer epidemic, but many other disease epidemics as well. Ultimately, the really great news is that you have far greater control over your health, and your risk of cancer, than you might think.
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