An Interview With James LaValle, RPh, CCN
James LaValle, RPh, CCN, is an internationally recognized educator and author in integrative and precision health. He’s best known for his personalized integrative therapies uncovering the underlying metabolic issues that keep people from feeling healthy and vital. He’s the founder of the Metabolic Code, a cloud-based software that gives clinicians a road map for creating personalized, targeted care plans. Mr. LaValle is also a thought leader in drug-nutrient depletion issues, and has published four books and three databases on this topic. He has over 35 years of experience incorporating natural and integrative therapies into various medical and business models. His latest research is in drug-induced microbiome disruption.
Chronic disease and aging are driven by free-radical damage. Also called reactive oxygen species, free radicals are unstable molecules with an uneven number of electrons. In their search for stability, they steal electrons and ultimately damage body cells, proteins, and DNA.
Unfortunately, there’s no avoiding free radicals. Even if you stay away from their external causes, like cigarette smoke, air pollution, and industrial chemicals, they’re a natural consequence of cellular metabolism.
But we do have some powerful, natural armor against free radicals. Our body’s antioxidant defense system involves enzymes and nutrients that work together to block the harmful effects of oxidative stress.
James LaValle, RPh, CCN, is an expert in performance nutrition and the creator of the Metabolic Code, a system to simplify the process of personalized nutrition. In creation of the Metabolic Code, it became clear to him that antioxidants were at the center of human physiology, health, and disease. In this interview with Element Senior Writer Sarah Cook, ND, he argues that we need to look beyond antioxidants as mere free-radical quenchers—and on to their deeper interactions with cellular antioxidant defense pathways.
ELEMENT: Before we get into the subject of antioxidants, could you tell us about the Metabolic Code and how you came to develop it?
JAMES LAVALLE: I’ve been developing personalized care plans for more than 35 years, and have seen thousands of patients. At my first big clinic in Ohio, we would see 300 people per week. I noticed clusters of patterns happening, and wanted to find a way to unravel the chemistry that would explain these patterns.
The thing is that most people don’t behave like drug or natural-product trials, where we control for variables and test one thing at a time. Instead, people are usually taking multiple drugs and supplements, and have a range of lifestyle habits. To unravel their biochemistry requires looking at many different variables—from biometrics to basic labs to functional labs.
How do you create a process that unwinds all of the different damages that have occurred in a lifetime? Whether the damage is from drug therapy, mold, environment, or , all of these processes are going on. In the end, these influences result in the complex illnesses we see in patients every day.
The Metabolic Code makes a complicated process simple. It’s a systematic and repeatable way to make sense of symptoms, biometrics, wearable data, basic bloodwork, and advanced functional labs all at once. We use an extensive questionnaire and then bring in results from blood sugar, lipids, liver, kidney, nutrients, food allergies, toxic heavy metals, and more.
The initial impetus for developing the Metabolic Code was to streamline the process for clinicians. It turns out that it also makes it much easier for patients to understand and get results quickly. The Metabolic Code helps to create targeted and personalized programs and then monitor how those programs change the biochemistry.
The way the Metabolic Code works is to take all the data and distill it down to five functional relationships, which we called TRIADS.
ELEMENT: What are the Metabolic Code TRIADS?
LAVALLE: The TRIADS are based on accepted relationships between organ systems in the body, with each TRIAD representing a domain of physiologic function.
TRIAD 1, for example, represents energy balance. It involves the adrenal glands, thyroid, and pancreas. It represents glucose balance and metabolism to the clinician, but energy level and weight to the patient.
The question I always ask is: “How far are you away from being well?” To answer that question, we need to see where a person’s chemistry is right now. Then we can determine the most important things to do to improve their metabolic reserve and durability and vitality. That’s how we optimize health—or practice what I call performance health.
ELEMENT: How do antioxidants and oxidative stress interact with the TRIADS and body systems?
LAVALLE: There’s a term used in the literature called metaflammation. It’s associated with a low level of ongoing , insulin resistance, loss of neuroplasticity, loss of bone, mitochondrial damage, and cellular aging. Another word that is often used to mean the same thing is inflamm-aging.
Part of the process of metaflammation or inflamm-aging is decreased efficiency of the mitochondria. Rather than producing the usual 38 packets of energy per glucose molecule burned, the metabolism switches to producing only two. It’s called the Warburg effect, and creates excess lactic acid and pyruvate.
The process of metaflammation interacts with all body systems and TRIADS. It accelerates when antioxidant defenses are incapacitated or blocked by an environmental burden. Then in a vicious cycle, the low level of inflammation triggers oxidative bursts. Reactive oxygen species are both drivers and products of metaflammation in all organs.
And oxidative stress is in the middle of it all.
ELEMENT: Why is oxidative stress in the middle?
LAVALLE: I’ll go through how oxidative stress interacts with the different body systems and TRIADS in a minute, but first it’s important to distinguish between where oxidative stress creates damage and where the oxidative stress originates.
For example, there may be oxidative stress affecting the brain tissue that originates from pro-inflammatory compounds generated in the gut barrier. It all comes back to this relationship between inflammation and oxidative stress. The person can take all the antioxidants they want, but not get results until they get to the source of where the is coming from.
To understand the signaling that creates the end damage from oxidative stress, it’s helpful to look at the nuclear factor kappa B (NF-kB) and nuclear factor erythroid 2–related factor 2 (Nrf2) pathways.
NF-kB is activated by the presence of reactive oxygen species. It initiates a cascade of signals, including cyclooxygenase (COX) and lipoxygenase (LOX), which promote inflammation in the tissues. The more we can downregulate or reduce the triggers for NF-kB, the better off we are.
Nrf2 is a transcription factor in the cell that’s bound to kelch-like ECH-associated protein 1
(Keap1). When Keap1 recognizes too much oxidative stress, it frees up Nrf2. The Nrf2 then goes to the cell nucleus and binds to the antioxidant-response element, which encodes genes that activate free-radical scavengers. To be fully competent to respond to these signals, the antioxidant defense network needs to be intact.
I bring up Nrf2 and NF-kB because we can influence these pathways with some antioxidants. Higher-end compounds, like resveratrol, green tea, and alpha-lipoic acid (ALA), do more than just squelch free radicals. They also inhibit NF-kB or upregulate Nrf2.
Advanced antioxidants like these not only keep the network of antioxidant defenses intact, but also help to turn off the engine that’s triggering and ongoing oxidative stress. They allow us to address metabolic dysfunction on a deeper level.
To make all of this practical, we need to identify in each person where the oxidative damage is being triggered and where the end damage is occurring. That’s exactly what the Metabolic Code helps us do.
ELEMENT: How do antioxidants interact with each of the five TRIADS of the Metabolic Code?
LAVALLE: As I mentioned earlier, TRIAD 1 refers to the adrenal glands, thyroid, and pancreas. This is a common place for oxidative stress to originate. Thyroid hormone is needed to burn fats, regulate glucose metabolism, and for insulin receptors to work properly. If thyroid receptors are blocked by an environmental toxin, insulin resistance can develop. With insulin resistance and elevated glucose, we start to create both oxidative damage and glycation damage.
and also trigger a progression of damage. Cortisol doesn’t directly create oxidative stress, but it triggers an immune shift where more inflammatory compounds are produced. Also, as cortisol goes up, thyroid function slows, and we get poor conversion of thyroxine (T4) to triiodothyronine (T3).
Damage to any of the organs in TRIAD 1 could lead to mitochondrial oxidative damage, inflammatory cytokines, and a shift in immune function toward a runaway inflammatory response. This can be the source of oxidative stress throughout the body, and can affect other body systems and TRIADS.
TRIAD 2 refers to the gut, immune system, and brain. This TRIAD can be both the source and recipient of oxidative damage. Direct oxidative damage from foods or pesticides or metals can directly trigger free-radical damage in the gut. Then one free radical begets another.
If superoxide anions are triggered in the gut, these reactive oxygen species can trigger more damaging free radicals, like peroxynitrites. These peroxynitrites then trigger vascular adhesion molecule 1 (VCAM-1), which remodels the vascular endothelium. What started in the gut has now spread to the arteries.
Another cascade that can begin in the gut involves lipopolysaccharide (LPS), which is released when bacteria die off in the gut. That can happen for many reasons, including reduced blood flow, food allergies, or drug therapies. We know that 25 percent of pharmaceutical drugs alter the .
When the bacteria die off, LPS circulates through the bloodstream as an endotoxin. It attaches to cells and triggers inflammatory chemicals that create more ongoing oxidative bursts. Elevated levels of circulating LPS can even start to influence autoimmune thyroiditis. This is how all of the body systems and TRIADS interact. We see these networks communicate with each other in a more damaging way.
For instance, let’s look at the brain. When somebody has high stress and is in sympathetic dominance, the fight-or-flight reaction can create oxidative bursts. But more importantly, the sympathetic response activates immune cells, known as microglial cells, in the brain. Microglial activation releases a cascade of and oxidative stress that damages the neurons.
We can’t lose sight of the fact that the body works as a whole metabolism. All of these systems work together and interact, driving a person either toward health or toward illness. If we want to address microglial cell activation in the brain, we need to use agents that not only dampen the effects of oxidative stress, but also reduce the inflammatory signaling that triggered the damage.
That’s why we use compounds like turmeric, astaxanthin, and green tea. They not only quench free radicals, but also work at the cellular level to shut down the signaling pathways that contribute to inflammation and oxidative bursts. It all comes back to the same question. How do we get to the source of oxidative stress in each individual?
ELEMENT: We’ve discussed the first two TRIADS. What’s the relationship between antioxidants and the other three TRIADS?
LAVALLE: TRIAD 3 refers to the cardiovascular, neurovascular, and pulmonary systems. These organs are often the victims of oxidative stress.
In endothelial tissue, oxidative stress leads to plaque formation. Damaged endothelium activates monocytes, which then activate macrophages, and the inflammatory cascade continues. Also, LPS can attach to cardiomyocytes to trigger inflammation in the tissues of the heart. No matter where the oxidative stress originates, it can damage the organs in TRIAD 3.
TRIAD 4 refers to the liver, lymph, and kidneys. The liver is not only important for , but also strikes at the heart of oxidative reduction management. It moves compounds through phase 1 and 2 to make damaging compounds excretable. The liver is also responsible for producing glutathione, one of the most important cellular antioxidants.
When we look at the role of the liver in antioxidant defenses, we need to recognize the importance of B vitamins and nutrient synergy. Even though B vitamins are not direct antioxidants, they’re required for the liver to carry out its role in detoxification and antioxidant defenses. Also, riboflavin is required for glutathione to enter red blood cells.
Once the liver prepares toxins for elimination, they proceed to the kidneys—which are extremely sensitive to the damaging effects of oxidative stress. The reason kidneys fail is because of a loss of redox poise. When a person loses the ability to manage oxidative stress in the nephrons of the kidneys, free radicals destroy these filtering cells. We need antioxidants to protect our redox potential.
One important consideration to protect the kidneys from oxidative damage is pH. Bound toxins that arrive for elimination through the kidneys (like mercury) can uncouple in an acidic environment, freeing them up to damage the nephrons of the kidney. Nutrients like magnesium and potassium can help maintain a healthy pH in the kidneys. Like B vitamins, these aren’t direct antioxidants, but are important because of their interaction with antioxidant defenses.
Lymphatics are included along with the liver and kidneys in TRIAD 4 because the lymph participates in cytokine balance and the patrol and maintenance of toxins. A lot of people think the lymph is passive, but it keeps the flow of redox to avoid recirculation of toxic compounds and species.
TRIAD 5 refers to testosterone, estrogen, and progesterone. These hormones interact with all of the body systems and influence antioxidant defenses more indirectly. For example, adequate testosterone is needed for insulin function.
On the other hand, supplementing bioidentical hormones in too high an amount can backfire and trigger inflammatory signals and free-radical damage. It comes back to the understanding that all body systems interact with one another, and too much of anything is not a good thing.
ELEMENT: What’s your perspective on the controversies of supplementing vitamins A and E?
LAVALLE: My first degree was in pharmacy, so I’m familiar with how we study drugs and nutrients. We usually get disappointing results when we supplement a single antioxidant or a synthetic compound. That’s been a problem with studies on vitamin E that only give d-alpha-tocopherol or vitamin A that only give synthetic beta-carotene. These studies ignore the broader family of carotenoids or the fact that vitamin E actually consists of mixed tocopherols and tocotrienols.
There’s also unnecessary controversy around pre-formed vitamin A. There was a study that came out 20years ago saying vitamin A could be teratogenic, and then five years after that saying that the results were skewed and inaccurate. Vitamin A is an essential nutrient. It acts as an antioxidant, supports epithelial tissues, and maintains immune competency and integrity. Many people don’t realize that we need vitamin A for vitamin D receptors to work effectively.
Can a person take too much vitamin E or vitamin A? Yes. These are fat-soluble nutrients. High levels of vitamin A can be stored in the liver and create toxicity. But anything can be damaging in excess. The idea that vitamin A is inherently damaging is a misconception. It’s an essential nutrient.
It comes back to the same questions: How far are you away from being well? What body systems are not performing at their best? What nutrients do you need to support those systems? The essential nutrients are often a good place to start.
ELEMENT: Could you describe the different classes of antioxidants?
LAVALLE: Glutathione is a master antioxidant, so we can look at nutrients that act as glutathione recyclers. The top two are) and alpha-lipoic acid (ALA). B vitamins are also needed to make glutathione because of methylation. Milk thistle can help with glutathione recycling. Glutathione can also be supplemented directly.
Intracellular antioxidants include NAC, selenium, and superoxide dismutase (SOD). Extracellular antioxidants include , tocopherols, carotenoids, lycopene, and curcumin.
The top mitochondrial antioxidant is . It participates in the electron transport chain to ensure you don’t drop those electrons while generating energy. Resveratrol, grapeseed extract (GSE), and bilberry all have direct antioxidant effects as well as the ability to stimulate mitochondrial biogenesis through the sirtuin pathway.
Antioxidants that interact with inflammatory pathways include curcumin, quercetin, and cat’s claw. Other antioxidants that influence the immune system are vitamins A, C, and E; carotenoids; and zinc. We can also consider adaptogens, like cordyceps and schisandra, for their antioxidant activity.
Then there are enzymatic antioxidants. The three main antioxidant enzymes in the body are catalase, superoxide dismutase (SOD), and glutathione peroxidase. SOD can be taken orally as a supplement. Also, these enzymes are dependent on nicotinamide adenine dinucleotide (NAD+), so we can support redox homeostasis by supporting healthy levels of NAD+. The supplement nicotinamide riboside can do this, and produce a strong response against the oxidative burst.
ELEMENT: What are your favorite antioxidants, and why?
LAVALLE: The essential nutrients make my list of favorites because the body needs them. The antioxidants in this category include vitamins A, C, and E, and zinc. Magnesium and B vitamins aren’t direct antioxidants, but interact with antioxidant defense systems.
My other favorites are antioxidants that play dual roles—both quenching free radicals and blocking the source of oxidative stress. Curcumin modulates inflammatory pathways. Green tea and its active compound, epigallocatechin gallate (EGCG), trigger the sirtuin pathway for mitochondrial biogenesis. ALA is a global antioxidant that squelches peroxynitrite ions, recycles glutathione, and supports cellular health of nephrons and nerves.
The most important point that I want clinicians to remember about antioxidants is that they do more than neutralize free radicals. Many antioxidants work on pathways that are more upstream, blocking the source of inflammation or ongoing oxidative stress. We need to look at antioxidants in this new light and choose them for their ability to address metabolic dysfunction at its source.