Stowers scientists are uncovering many mysteries underlying metabolism. Here we ask five questions to unravel metabolism and its complexities.
02 February 2023
By Rachel Scanza, Ph.D.
Blue zones. Coined in 2004, this term refers to micro-regions around the world where inhabitants are significantly healthier and frequently live beyond 100 years. The diets within these populations ranging from Okinawa, Japan to several regions in southern Italy and even to Loma Linda, California are primarily plant-based and low in sugar, protein, alcohol, and, most importantly, calories.
More frequently, some scientists are investigating the interplay of
diets that mimic fasting with lowered risks of diseases linked to
metabolism. Currently popular fads include the “Keto Diet” and
Although we use the word metabolism ubiquitously in our daily lives, how many of us know what it actually means? The Stowers Institute for Medical Research
is at the forefront of uncovering metabolic mysteries.
What is metabolism?
In simple terms, metabolism is the sum of the chemical reactions that
occur within and between every single cell in our body, governing how
energy and cell products are created and consumed to perform necessary
tasks. In fact, metabolism is at play in the very act of reading this
Each project performed, from the assembly of a protein to the flex of
a muscle, requires an exchange of energy. The set of reactions that
generate or utilize energy are referred to as metabolic reactions. And,
for every task, many elements are involved, at different points in time
and space, rendering an intuitively simple process much more complex
than we realize.
Several Stowers scientists are actively investigating metabolism at the molecular level with the concession that we still have a lot to learn.
How has metabolism evolved and why is that important?
Evolutionary biologist Andreas Wagner, Ph.D., stated that “Life is
the combination of metabolism and replication.” The myriad diversity of
organisms found today arose from those very first forms of life.
From the primordial soup that characterized elementary life on our
planet, these ancient “organisms” manufactured carbohydrates from UV
radiation and other external energy sources like lightning.
Today, plants harness energy from the sun to produce sugar during
photosynthesis. People, on the other hand—even plant-eating people or
carnivorous cattle consumers—must intake energy in the form of food, be
it legumes or beef, to power the countless cellular functions that keep
One example of the interplay between metabolism and evolution
involves river-dwelling surface fish in locations all around the globe
that have flooded into underground caves on timespans ranging from
100,000 to one million years ago. The Stowers Institute is home to the
largest cavefish facility in the world, housing fish from the Molino,
Pachón, and Tinaja caves in central Mexico.
The lab of Associate Investigator Nicolas Rohner, Ph.D.,
at the Stowers Institute studies many different aspects of metabolism
in cavefish. In the absence of light, predators, a reliable nutrient
supply, and water currents, these fish have evolved remarkably similar
genetic adaptations, completely independently from one another, to
published last year examined cavefish liver tissue for clues to how
these fish display extreme characteristics resembling diabetes and high
body fat. The researchers found that non-coding regions of DNA were
mutated, likely circumventing melanin production for increased energy
from Stowers revealed that skeletal muscle in cavefish has undergone
genetic reprogramming to enable swift swimming speeds and muscular
endurance despite significant decreases in muscle mass and increases in
Is it as simple as food in, food out?
Most of us are familiar with “calories in” vs. “calories out” as a
convenient metric for metabolism and weight control. When the two are
equal, weight should remain constant, while an inequality in the former
or the latter should result in a net weight gain or loss, respectively.
In reality, metabolism in humans and in nearly all organisms is a great deal more complex.
Metabolism at the cellular level is integral for gene expression and
subsequent synthesis of proteins required for cellular function. DNA is
not the familiar freely floating double helix many envision from high
school biology or Jurassic Park; it is neatly and compactly packaged
into chromatin—the protein-DNA complex that makes up chromosomes.
Postdoctoral Researcher Michael Church, Ph.D., from the Workman Lab
investigates the role of chromatin modifying molecules. Depending on
nutritional intake of, for example, carbohydrates vs. proteins,
different metabolic pathways are activated that produce different
metabolites, all designed to increase the access of DNA to initiate
transcription, and consequently protein synthesis.
It is not as simple as food in vs. food out. “Food is anything but
simple!” said Church. “For example, just changing the composition of gut
microbes can alter the cocktail of nutrients that enter your
intestines, even without changing your diet.” However, the food we
choose to consume can and does impact metabolism.
Why are we prone to diseases like diabetes?
Genetic adaptations take time. A lot of time. And humans are, from an evolutionary standpoint, in their infancy.
While species like cavefish
and nectar bats
can consume and store large amounts of sugar-rich nutrients—and remain
healthy while displaying traits like high blood glucose, insulin
resistance, and increased fat storage—these same traits in humans can
result in disease.
Historically, humans have been able to adapt, albeit not genetically,
to “feast or famine” periods. Today, however, feast has replaced famine
in many regions around the globe.
“Humans are not adapted to an environment where high-calorie food is
abundant. As a consequence, we develop diseases such as diabetes and
metabolic syndrome,” said Rohner.
Quite simply, we haven’t had enough time.
Can we change our metabolism?
Yes. And no.
Small genetic differences contribute to the natural variation from
person to person, including metabolism. These tiny changes in gene
expression and thus enzyme availability cause clear and easily
observable “metabotypes”: slim, heavy, muscular, etc.
We can’t actually change our metabolism—the underlying genetics governing metabolism—at least not yet. However, we can observe certain practices that can alter metabolism in the short term.
Popular dietary practices in current circulation are intermittent
fasting (IF) and the keto diet. The former limits food consumption to
strict time intervals and the latter requires consuming protein and
fat—goodbye fruits, legumes, pasta, bread, and sugar. Both diets induce a
metabolic pathway called ketosis. Metabolism is primarily limited to
generating ketones from fat that serve as alternative metabolites.
Essentially, these diets trick your body into starvation-mode where you
metabolize fat stores.
“It’s very hard to alter one’s metabolism, which is why most diets,
if not consistently maintained, are bound to fail,” said Rohner. “My
research on cavefish inspired me to adopt IF. While this isn’t for
everyone, it works for me.”
Additional factors like sleep and stress generate hormones impacting
metabolism. Calorie restriction not only can alter metabolism but is
linked to longer life.
No, we can’t change our metabolism today, but we can augment it for
the duration of practicing measures of austerity. At some point down the
line, however, humans may evolve metabolic adaptations that bypass disease