summarize this "More than two decades ago, a University of Colorado nephrologist named
Rick Johnson noticed that fructose consumption appeared to be an especially
powerful driver not only of high blood pressure but also of fat gain. “We
realized fructose was having effects that could not be explained by its calorie
content,” Johnson says. The culprit seemed to be uric acid. Other mammals,
and even some other primates, possess an enzyme called uricase, which helps
them clear uric acid. But we humans lack this important and apparently
beneficial enzyme, so uric acid builds up, with all its negative consequences.
Johnson and his team began investigating our evolutionary history, in
collaboration with a British anthropologist named Peter Andrews, a retired
researcher at the Natural History Museum in London and an expert on
primate evolution. Others had observed that our species had lost this uricase
enzyme because of some sort of random genetic mutation, far back in our
evolutionary past, but the reason why had remained mysterious. Johnson and
Andrews scoured the evolutionary and fossil record and came up with an
intriguing theory: that this mutation may have been essential to the very
emergence of the human species.
The story they uncovered was that, millions of years ago, our primate
ancestors migrated north from Africa into what is now Europe. Back then,
Europe was lush and semitropical, but as the climate slowly cooled, the forest
changed. Deciduous trees and open meadows replaced the tropical forest, and
the fruit trees on which the apes depended for food began to disappear,
especially the fig trees, a staple of their diets. Even worse, the apes now had
to endure a new and uncomfortably cold season, which we know as “winter.”
In order to survive, these apes now needed to be able to store some of the
calories they did eat as fat. But storing fat did not come naturally to them
because they had evolved in Africa, where food was always available. Thus,
their metabolism did not prioritize fat storage.
At some point, our primate ancestors underwent a random genetic
mutation that effectively switched on their ability to turn fructose into fat: the
gene for the uricase enzyme was “silenced,” or lost. Now, when these apes
consumed fructose, they generated lots of uric acid, which caused them to
store many more of those fructose calories as fat. This newfound ability to
store fat enabled them to survive in the colder climate. They could spend the
summer gorging themselves on fruit, fattening up for the winter.
These same ape species, or their evolutionary successors, migrated back
down into Africa, where over time they evolved into hominids and then Homo
sapiens—while also passing their uricase-silencing mutation down to us
humans. This, in turn, helped enable humans to spread far and wide across
the globe, because we could store energy to help us survive cold weather and
seasons without abundant food.
But in our modern world, this fat-storage mechanism has outlived its
usefulness. We no longer need to worry about foraging for fruit or putting on
fat to survive a cold winter. Thanks to the miracles of modern food
technology, we are almost literally swimming in a sea of fructose, especially
in the form of soft drinks, but also hidden in more innocent-seeming foods
like bottled salad dressing and yogurt cups.
[*4]
Whatever form it takes, fructose does not pose a problem when consumed
the way that our ancestors did, before sugar became a ubiquitous commodity:
mostly in the form of actual fruit. It is very difficult to get fat from eating too
many apples, for example, because the fructose in the apple enters our system
relatively slowly, mixed with fiber and water, and our gut and our metabolism
can handle it normally. But if we are drinking quarts of apple juice, it’s a
different story, as I’ll explain in a moment.
Fructose isn’t the only thing that creates uric acid; foods high in chemicals
called purines, such as certain meats, cheeses, anchovies, and beer, also
generate uric acid. This is why gout, a condition of excess uric acid, was so
common among gluttonous aristocrats in the olden days (and still today). I
test my patients’ levels of uric acid, not only because high levels may promote
fat storage but also because it is linked to high blood pressure. High uric acid
is an early warning sign that we need to address a patient’s metabolic health,
their diet, or both.
Another issue is that glucose and fructose are metabolized very differently
at the cellular level. When a brain cell, muscle cell, gut cell, or any other type
of cell breaks down glucose, it will almost instantly have more ATP
(adenosine triphosphate), the cellular energy “currency,” at its disposal. But
this energy is not free: the cell must expend a small amount of ATP in order
to make more ATP, in the same way that you sometimes have to spend
money to make money. In glucose metabolism, this energy expenditure is
regulated by a specific enzyme that prevents the cell from “spending” too
much of its ATP on metabolism.
But when we metabolize fructose in large quantities, a different enzyme
takes over, and this enzyme does not put the brakes on ATP “spending.”
Instead, energy (ATP) levels inside the cell drop rapidly and dramatically.
This rapid drop in energy levels makes the cell think that we are still hungry.
The mechanisms are a bit complicated, but the bottom line is that even
though it is rich in energy, fructose basically tricks our metabolism into
thinking that we are depleting energy—and need to take in still more food
and store more energy as fat.
[*5]
On a more macro level, consuming large quantities of liquid fructose
simply overwhelms the ability of the gut to handle it; the excess is shunted to
the liver, where many of those calories are likely to end up as fat. I’ve seen
patients work themselves into NAFLD by drinking too many “healthy” fruit
smoothies, for the same reason: they are taking in too much fructose, too
quickly. Thus, the almost infinite availability of liquid fructose in our already
high-calorie modern diet sets us up for metabolic failure if we’re not careful
(and especially if we are not physically active).
—
I sometimes think back to that patient who first introduced me to fatty liver
disease. He and Samuel Zelman’s Patient Zero, the man who drank a dozen
Cokes a day, had the same problem: they consumed many more calories than
they needed. In the end, I still think excess calories matter the most.
Of course, my patient was in the hospital not because of his NAFLD, but
because of his colon cancer. His operation turned out beautifully: we removed
the cancerous part of his colon and sent him off to a speedy recovery. His
colon cancer was well established, but it had not metastasized or spread. I
remember the attending surgeon feeling pretty good about the operation, as
we had caught the cancer in time. This man was maybe forty or forty-five,
with a long life still ahead of him.
But what became of him? He was obviously also in the early stages of
metabolic disease. I keep wondering whether the two might have been
connected in some way, his fatty liver and his cancer. What did he look like,
metabolically, ten years before he came in for surgery that day? As we’ll see
in chapter 8, obesity and metabolic dysfunction are both powerful risk factors
for cancer. Could this man’s underlying metabolic issues have been fueling
his cancer somehow? What would have happened if his underlying issues,
which his fatty liver made plain as day, had been recognized a decade or
more earlier? Would we have ever even met?
It seems unlikely that Medicine 2.0 would have addressed his situation at
all. The standard playbook, as we touched on in chapter 1, is to wait until
someone’s HbA1c rises above the magic threshold of 6.5 percent before
diagnosing them with type 2 diabetes. But by then, as we’ve seen in this
chapter, the person may already be in a state of elevated risk. To address this
rampant epidemic of metabolic disorders, of which NAFLD is merely a
harbinger, we need to get a handle on the situation much earlier.
One reason I find value in the concept of metabolic syndrome is that it
helps us see these disorders as part of a continuum and not a single, binary
condition. Its five relatively simple criteria are useful for predicting risk at the
population level. But I still feel that reliance on it means waiting too long to
declare that there is a problem. Why wait until someone has three of the five
markers? Any one of them is generally a bad sign. A Medicine 3.0 approach
would be to look for the warning signs years earlier. We want to intervene
before a patient actually develops metabolic syndrome.
This means keeping watch for the earliest signs of trouble. In my patients,
I monitor several biomarkers related to metabolism, keeping a watchful eye
for things like elevated uric acid, elevated homocysteine, chronic
inflammation, and even mildly elevated ALT liver enzymes. Lipoproteins,
which we will discuss in detail in the next chapter, are also important,
especially triglycerides; I watch the ratio of triglycerides to HDL cholesterol
(it should be less than 2:1 or better yet, less than 1:1), as well as levels of
VLDL, a lipoprotein that carries triglycerides—all of which may show up
many years before a patient would meet the textbook definition of metabolic
syndrome. These biomarkers help give us a clearer picture of a patient’s
overall metabolic health than HbA1c, which is not very specific by itself.
But the first thing I look for, the canary in the coal mine of metabolic
disorder, is elevated insulin. As we’ve seen, the body’s first response to
incipient insulin resistance is to produce more insulin. Think back to our
analogy with the balloon: as it gets harder to get air (glucose) into the balloon
(the cell), we have to blow harder and harder (i.e., produce more insulin). At
first, this appears to be successful: the body is still able to maintain glucose
homeostasis, a steady blood glucose level. But insulin, especially postprandial
insulin, is already on the rise.
One test that I like to give patients is the oral glucose tolerance test, or
OGTT, where the patient swallows ten ounces of a sickly-sweet, almost
undrinkable beverage called Glucola that contains seventy-five grams of pure
glucose, or about twice as much sugar as in a regular Coca-Cola.
[*6] We then
measure the patient’s glucose and their insulin, every thirty minutes over the
next two hours. Typically, their blood glucose levels will rise, followed by a
peak in insulin, but then the glucose will steadily decrease as insulin does its
job and removes it from circulation.
On the surface, this is fine: insulin has done its job and brought glucose
under control. But the insulin in someone at the early stages of insulin
resistance will rise very dramatically in the first thirty minutes and then
remain elevated, or even rise further, over the next hour. This postprandial
insulin spike is one of the biggest early warning signs that all is not well.
Gerald Reaven, who died in 2018 at the age of eighty-nine, would have
agreed. He had to fight for decades for insulin resistance to be recognized as a
primary cause of type 2 diabetes, an idea that is now well accepted. Yet
diabetes is only one danger: Studies have found that insulin resistance itself is
associated with huge increases in one’s risk of cancer (up to twelvefold),
Alzheimer’s disease (fivefold), and death from cardiovascular disease (almost
sixfold)—all of which underscores why addressing, and ideally preventing,
metabolic dysfunction is a cornerstone of my approach to longevity.
It seems at least plausible that my patient with the fatty liver had
developed elevated insulin at some point, well before his surgery. But it is also
extremely unlikely that Medicine 2.0 would have even considered treating
him, which boggles my mind. If any other hormone got out of balance like
this, such as thyroid hormone or even cortisol, doctors would act swiftly to
rectify the situation. The latter might be a symptom of Cushing’s disease,
while the former could be a possible sign of Graves’ disease or some other
form of hyperthyroidism. Both of these endocrine (read: hormone) conditions
require and receive treatment as soon as they are diagnosed. To do nothing
would constitute malpractice. But with hyperinsulinemia, for some reason, we
wait and do nothing. Only when type 2 diabetes has been diagnosed do we
take any serious action. This is like waiting until Graves’ disease has caused
exophthalmos, the signature bulging eyeballs in people with untreated
hyperthyroidism, before stepping in with treatment.
It is beyond backwards that we do not treat hyperinsulinemia like a bona
fide endocrine disorder of its own. I would argue that doing so might have a
greater impact on human health and longevity than any other target of
therapy. In the next three chapters, we will explore the three other major
diseases of aging—cardiovascular disease, cancer, and neurodegenerative
diseases—all of which are fueled in some way by metabolic dysfunction. It
will hopefully become clear to you, as it is to me, that the logical first step in
our quest to delay death is to get our metabolic house in order.
The good news is that we have tremendous agency over this. Changing
how we exercise, what we eat, and how we sleep (see Part III) can completely
turn the tables in our favor. The bad news is that these things require effort to
escape the default modern environment that has conspired against our ancient
(and formerly helpful) fat-storing genes, by overfeeding, undermoving, and
undersleeping us all."