Metabolical: The Lure and the Lies of Processed Food, Nutrition, and Modern Medicine

by Robert H. Lustig

Big Pharma is the first of the three immoral hazards delineated in this book, creating the problem, and making money off the misfortunes of others.

the adult American population is 67 percent overweight, but the data argues that 88 percent of the population exhibits some level of metabolic dysfunction. Is obesity the problem, or the symptom

what do the doctors tell the other 21 percent who aren’t obese but still metabolically ill? What disease do they have? After all, if doctors don’t know how to diagnose, treat, or prevent an unknown disease, why would they even bring it up?

Metabolic dysfunction is the “disease without a name.” The cells of the body, and often of the brain, are sick, due to eight—count ’em, eight—intracellular processes that have gone awry. These eight processes are not mutually exclusive—often if you have one going on, you likely have more than one.

these eight processes, when working right, contribute to longevity; but when not working right underlie the various chronic diseases that result in mortality. They’re not considered diseases per se—as they don’t have an easy lab test or biomarker. They don’t have an ICD-11 code, so they aren’t reimbursable. They don’t have a drug target (see Chapter 10), so doctors don’t talk about any of them with their patients—because why would you want to bring up something you can’t solve? It recalls a saying I learned while I was a visiting professor in Paris, “If there is no solution, there is no problem.”

Each of these eight processes can work for you, in which case you’ll live to be one hundred playing tennis—or against you, in which case you’ll be disabled, depressed, on dialysis, or dead before your time.

energy metabolism only, which is the root of all eight subcellular pathways.

But if glucose is in short supply and insulin levels are low, then adipose tissue will give up some of its stored fatty acids to enter the bloodstream, and the liver will turn those fatty acids into ketones, which then seep back into the bloodstream, so that any cell can burn those ketones instead, even without insulin.

Why do we get cataracts and wrinkles as we get older? Each of these is an example of an undeniable and inevitable fact of life—the Maillard or glycation or browning or caramelization reaction. All four terms describe the same process, which is the primary process of aging.

But you can slow this process down—and if you’re successful, you’ll be a lot healthier for a lot longer.

The question is not if the Maillard reaction will occur, but rather how fast.

And this is where the metabolic differences between glucose and fructose becomes important (see Chapters 2 and 12). One might think that glucose and fructose, both being molecules found in dietary sugar (sucrose, high-fructose corn syrup, honey, maple syrup, agave—they’re all metabolically the same; take your pick), would drive this reaction at the same rate. You would be very wrong. Yes, they’re both carbohydrates, and yes, they both bind to proteins, but that’s where their similarities end. Because glucose has a six-member-ring structure (see Fig. 7–2), it’s more stable and engages in the Maillard reaction relatively slowly. Conversely, fructose’s five-member ring is more easily broken apart, and engages in the Maillard reaction seven times faster than glucose.

when it comes to aging, fructose is worse than glucose, and therefore sugar is worse than starch. That doesn’t make glucose “good”—it raises insulin and drives obesity—but compared to fructose, it’s a walk in the park.

Oxygen radicals are a standard by-product of three normal reactions in the body: glycation; energy metabolism in our mitochondria; and iron metabolism (equivalent to rusting, which is constantly occurring in all of our cells). Furthermore, oxygen radicals are formed in response to anything that causes inflammation. Thus, each cell in our body ordinarily has to deal with an oxygen radical pool; if unleashed they would kill us pretty quickly.

Chronic disease is mitochondrial dysfunction, and mitochondrial dysfunction is chronic disease. They are one and the same.

The single best stimulus to make more and fresh mitochondria is exercise—but even your mitochondria can’t outrun a bad diet (see

fructose (in processed food) makes twice as much liver fat as does glucose.

The sicker your mitochondria, the earlier you die. The organs that need mitochondria and energy production the most are the brain and hormone-secreting organs—because neurotransmission and hormone secretion are energetically expensive. If the mitochondrial DNA is defective, you end up with a class of nasty diseases known as mitochondrial encephalomyopathies.

Insulin’s main job is actually to store energy for a rainy day.

Just two organs in your body need insulin to function: the liver and adipose tissue. Too much insulin can get in the way, forcing glucose clearance from the bloodstream into tissues. It can also lead to hypoglycemia (low blood glucose) and inadequate glucose delivery to the brain, which can make you dizzy or unconscious or seize or die, depending on its severity. The pancreas senses the drop in the blood glucose, and stops releasing insulin before you lose consciousness.

nowadays, more often than not, the opposite problem occurs; different types of cells are not responding to the insulin in the bloodstream. This is called insulin resistance. When glucose can’t get into certain cells, those cells starve, which leads to organ dysfunction. When the liver or muscles are resistant, glucose builds up in the blood, leading to diabetes. The fact of the matter is that insulin resistance is...

Various problems that can lead to defective insulin signaling are: obesity; chronic stress; environmental chemicals that drive weight gain (obesogens like estrogen, bisphenol A [BPA], phthalates, PBDE flame retardants); and, our favorite, processed food

Membranes can be damaged through two mechanisms: the lipids themselves are damaged either from toxins or from oxidative stress (see Oxidative Stress); or the lipids are inflexible, like rubber tubing where cracks appear due to plastic that has gotten old and dried out. Membranes should be flexible and malleable like a balloon, called membrane fluidity—they should give somewhat when poked from one direction. When they don’t, they can burst.

Problems with lipids can damage outer membranes in one of two ways. First, saturated fatty acids (which are different from saturated fats; see Chapter 12) are completely flexible because they don’t have any double bonds, which normally apply a degree of inflexibility to a fat’s structure.

Unsaturated fats are almost always better for you than saturated ones, which themselves are none too problematic in regard to metabolic syndrome. Because of their cis-double bonds, unsaturated fatty acids have fixed angles built into them, which prevents them from layering.

While we need an inflammatory response (or we would be eaten by the maggots), unfortunately there are four downsides. 1) The process kills normal tissues, too, which can lead to long-standing damage after the invader is cleared (e.g., kidney disease after E. coli, coronary aneurysms after Kawasaki disease, and now we are learning about long-term damage with COVID-19).

The inflammatory reaction will cause breaks in the intestinal barrier, allowing toxins and bacteria to pass across the intestinal wall into the bloodstream; they then head to the liver and cause insulin resistance, a process known as leaky gut. Leaky gut is one reason for the dramatic increase in food allergies and autoimmune disease in people (see

Body fat (subcutaneous or visceral fat) can release palmitate, an inflammatory lipid, which in turn drives up the inflammatory response.

palmitate is the real bad actor in the story of metabolic syndrome

Lots of effort has been placed on looking for genetic reasons behind metabolic syndrome, but the studies say only 15 percent is genetic—the rest is environmental. But environment can change genes as well, through a phenomenon called epigenetics. Epigenetics refers to changes in the areas around our genes that can cause them to be turned on or off, usually inappropriately, altering responses to these pathologies, and which over time can result in the development of various diseases.

In some cases, environmental factors alter the epigenetic programming of germ cells in the sperm or egg, and alterations in disease can appear in future generations without further direct exposure. This is known as transgenerational epigenetic inheritance. So far, it’s been shown to affect as many as four generations going into the future. So it’s not just what you ate; it’s what your mother ate.

Clearing biological waste products is a process known as autophagy, and it plays a key role in healthy aging, especially in the brain. The brain uses more energy than any other organ, and so there are lots of mitochondria, oxygen radicals, and therefore lots of damage in it.

Omega-3 fatty acids (see Chapter 19), which we need for healthy brain functioning, are particularly susceptible to damage—which equals lots of cleanup.

to improve metabolism and slow aging, it’s essential to get rid of the old mitochondria by autophagy. In fact, people who clear their mitochondria more efficiently live longer.

vitamin D deficiency is associated with cellular aging; and vitamin D appears to play an important role in promoting autophagy, by increasing calcium influx into old cells, which induces a cellular program to purposefully kill it. Paradoxically, vitamin B1 deficiency accelerates neurodegeneration, while supplementation appears to promote autophagy and slow neurodegeneration, by reducing oxygen radical formation.

all eight processes are related to chronic disease, and also related to each other and to food. See a pattern here? These are the true diseases of processed food; they’re just not called diseases or taught in medical school. But they should be taught before any mention of any drug, so that medical students can triangulate, “How does this drug impact these eight processes?”

Food drives both illness and wellness; it’s the poison and the antidote. Metabolic syndrome could colloquially be redefined as cells eating badly, as every one of the eight subcellular pathologies is made worse by providing the wrong food in the wrong place at the wrong time.

there are really only two processes that handle energy properly—growing or burning.

What determines when a cell grows or burns, and what determines when a cell lives or dies? What if a cell is burning when it should be growing, and living when it should be dying, or vice versa? Any perturbation of the growing/burning or living/dying pattern will lead to disease. It’s through this lens where we find the clues to the real reasons for metabolic syndrome (spoiler alert: it’s processed food!), and also for both treatment and prevention.

Does life need oxygen? Plant life clearly doesn’t. In fact, green plants need carbon dioxide for photosynthesis, making oxygen as the by-product. But does animal life need oxygen? The first clue to this puzzle came in 1924. German biochemist Otto Warburg made an astounding observation—cancer cells didn’t need oxygen to grow. While Warburg never figured out why this was the case, his observation was important enough that he won the 1931 Nobel Prize in Physiology or Medicine.

So regular cells need oxygen, but cancerous ones don’t? Aren’t cancer cells just regular cells sped up? They divide way faster than normal, which is why some chemotherapies work—they poison the dividing process (called mitosis). But how can growing cells not need oxygen? Doesn’t every cell need oxygen? The answer is a resounding no. In fact, there’s very little oxygen in the gut. The intestinal microbiome has adapted to it; 99 percent of the bacteria in our intestine, called obligate anaerobes, don’t need oxygen. In fact, many bacteria grow just fine without it and don’t have mitochondria.

Any idea about what cells grow even faster than cancer cells? Fetal cells.

The discovery of the metabolic signal for this effect that drives cancer and fetal cells to grow without oxygen is so important the Nobel Prize was awarded to its discoverers (Gregg Semenza, William Kaelin Jr., and Peter Ratcliffe) in 2019.

There are only four states of increased lactic acid production in humans: post-exercise, cancer, mitochondrial diseases like Kearns-Sayre syndrome (see Chapter 7), and metabolic syndrome—because that’s mitochondrial dysfunction as well.

sarcopenia, or loss of muscle mass. As people advance into their seventies, they can lose half their muscle mass, which renders them frail and susceptible to falling and fracture. To treat this, exercise physiologists have started putting tight bands around the patient’s arms and legs with low-intensity resistance and endurance training. Lo and behold, muscles increase in mass and strength—because depriving muscle cells of oxygen switched them from burning to growing.

Two Metabolic Programs—One for Growth, One for Burning

Both of these pathways, glycolysis for growth and the Krebs cycle for burning, are adaptive.

those eight subcellular pathologies of Chapter 7 become maladaptive. And this is where processed food becomes maladaptive.

When the three checkpoints (which we’ll call Alpha, Bravo, Charlie) are coordinated in one direction, you get growth. When they are coordinated in the opposite direction, you get burning. But when they are uncoordinated, that’s when you get a traffic jam and chronic metabolic disease happens.

a cell has plenty of energy but limited oxygen or mitochondria, it may decide to divide; while if a cell has adequate oxygen and glucose, it may just hang out. Finally, if a cell has limited energy and is getting old, it may decide to die to make room for new ones (autophagy). What signals this three-path Rubicon of fate? That’s the job of the third checkpoint, mTOR, which determines a cell’s commitment to growth, quiescence, or death.