Beyond “What Is Low?”: Why Nutrients Become Depleted in the First Place

A recent narrative review in The American Journal of Clinical Nutrition asked an important question: can biomarkers help individualize nutritional therapy in disease-related malnutrition?

The authors reviewed markers such as CRP, IL-6, creatinine, albumin, prealbumin, red cell distribution width, handgrip strength, CT-based muscle assessment, endocrine markers, catabolic markers, metabolomics, and AI-supported prediction models.

Their proposal is timely: nutritional therapy should become more individualized, and biomarkers may help predict prognosis and treatment response.

But the review also exposes a deeper knowledge gap in nutritional science.

The problem is not only that we need “better biomarkers.”

The problem is that we still lack a framework for understanding why biomarkers become abnormal and why nutritional replacement sometimes fails to restore recovery.

In other words, the deeper question is not:

What nutrient is depleted?

The deeper question is:

Why is this nutrient depleted, redistributed, unavailable, poorly retained, or not being converted into recovery?

The biomarker problem in nutrition

Modern nutrition science is increasingly rich in data.

We can measure inflammatory markers, blood proteins, hormones, kidney function, amino acids, organic acids, minerals, fatty acids, vitamins, metabolomic profiles, and body-composition markers.

Yet the more we measure, the more confusing the picture can become.

One patient may have low albumin, low zinc, low magnesium, low vitamin D, high CRP, low muscle mass, altered thyroid hormones, and abnormal amino acids. Another may have similar nutritional intake but a completely different biomarker pattern. A third may take many supplements, improve the laboratory numbers, but still feel fatigued, inflamed, weak, or unable to recover.

This is why the review’s conclusion is so important. The authors note that specific blood biomarkers for personalized disease-related malnutrition care are not yet routinely incorporated into clinical practice. They also emphasize that albumin and prealbumin are strongly influenced by inflammation, liver function, fluid balance, and metabolism, and therefore do not simply reflect nutritional adequacy.

That is the key point: many so-called “nutrition markers” are not just nutrition markers. They are state markers.

They tell us something about the organism’s current adaptive condition.

The common clinical trap: test everything, supplement everything

A similar problem appears in everyday nutritional and functional medicine practice.

A patient performs a broad serum micronutrient panel. The report shows low or borderline levels of several nutrients. The treatment plan then becomes a list of replacements:

Low zinc? Give zinc.

Low magnesium? Give magnesium

.Low vitamin D? Give vitamin D.

Low B vitamins? Give B-complex.

Low amino acids? Give protein powder or amino acids.

This approach can be useful when there is a true deficiency. But it can also become misleading if we stop there.

Because the body is not a storage cabinet. Nutrients are not just inventory items. They are absorbed, transported, activated, retained, redistributed, consumed, recycled, and used according to biological priorities.

A low nutrient level may reflect poor intake. But it may also reflect poor absorption, gut inflammation, renal loss, oxidative demand, immune activation, poor transport-protein production, mitochondrial stress, endocrine adaptation, or chronic allostatic burden.

So the question should not stop at:

“What is low?”

It should move to:

“What adaptive burden is making it low?”“Why has the system failed to restore it?”“Can the body currently use this nutrient for repair?”“Or is it still locked in stress-defense mode?”

Nutrient depletion as a downstream signal

In a recovery-based model, nutrient depletion is often a downstream sign of unresolved adaptive demand.

For example, magnesium may be depleted because of stress physiology, poor intake, gastrointestinal loss, renal wasting, medication effects, or high ATP-related demand.

Zinc may be low because of poor intake, gut dysfunction, inflammation, immune redistribution, metallothionein response, or impaired protein transport.

Iron markers may be abnormal not only because of iron deficiency, but also because inflammation changes iron distribution and transport.

Albumin, prealbumin, and transferrin are even more revealing. They are often interpreted as “protein nutrition” markers, but under stress, the liver may reprioritize protein synthesis away from transport and maintenance functions toward acute-phase defense. This is not simply malnutrition in the calorie-counting sense.

It is adaptive triage.

The body is asking:

“What must be protected first?”

Defense, circulation, glucose supply, immune response, tissue repair, detoxification, reproduction, muscle maintenance, and long-term resilience do not all receive equal priority during chronic stress.

When reserve is limited, biology triages.

The missing framework: finite bioenergetic reserve

This is where the framework of finite bioenergetic reserve becomes essential.

Every stress response requires energy. Inflammation requires energy. Immune activation requires energy. Detoxification requires energy. Tissue repair requires energy. Digestion, absorption, transport, hormone conversion, redox control, and mitochondrial ATP production all require energy.

When the body has enough reserve, it can respond, adapt, and recover.

But when demand remains high and recovery is incomplete, the system enters bioenergetic constraint. The body may still function, but it functions by reallocating resources. Some systems remain protected, while others are downregulated, sacrificed, delayed, or poorly repaired.

This is the foundation of Exposure-Related Malnutrition, or ERM.

ERM proposes that malnutrition-like patterns can emerge not only from insufficient intake, but from chronic adaptive demand, impaired utilization, transport limitation, redox burden, mitochondrial throughput constraint, and reduced recovery capacity.

In this view, nutrient depletion is not only a supply problem. It can be a stress-adaptation problem.

From primary markers to secondary domains

The practical solution is not to abandon biomarkers. It is to interpret them differently.

Primary clinical markers tell us what is abnormal.

Secondary functional domains help us understand why the pattern exists.

Primary marker pattern	Secondary domain interpretation
CRP, IL-6, TNF-α, cortisol, GDF15	Vital/stress domain: active defense, inflammation, catabolism, reduced feeding tolerance
Albumin, prealbumin, transferrin, RDW, amino acid availability	General metabolic reserve / transport domain: impaired carrier capacity, repair substrate availability, hepatic allocation
Glucose, insulin, triglycerides, uric acid, lactate, redox-related markers	Metabolic-routing domain: congestion, substrate pressure, mitochondrial or redox burden
Handgrip strength, muscle mass, phase angle, body composition	Long-term functional domain: structural reserve, muscle sacrifice, recovery capacity
T3, sex hormones, sleep rhythm, autonomic signs	Adaptation/recovery domain: whether the body is conserving energy, restoring reserve, or remaining in stress mode

This shift helps solve the “single biomarker” problem.

There may not be one major marker of nutritional depletion because the body does not fail in one dimension. It adapts through patterns.

A high CRP does not simply mean “inflammation.” It may mean that the vital/stress domain is still dominant.

Low albumin does not simply mean “eat more protein.” It may mean that general metabolic reserve and transport capacity are constrained.

Low handgrip strength does not simply mean “muscle weakness.” It may mean long-term functional reserve has been sacrificed.

Low micronutrients do not simply mean “replace everything.” They may mean that the body is losing, consuming, redistributing, or failing to utilize nutrients because it has not returned to a recovery state.

Allostatic triage: why recovery fails

Allostasis is the body’s ability to maintain stability through change. It is how we adapt to stress.

But adaptation is not free.

When stress is repeated or prolonged, the body pays a biological cost. Energy and nutrients are redirected toward immediate survival priorities: inflammation, immune defense, blood pressure control, glucose availability, oxidative stress management, and tissue protection.

This is allostatic triage.

The body prioritizes short-term survival over long-term maintenance.

That is why someone can have many “deficiencies” on testing, take many supplements, and still not recover. The issue may not be insufficient pills. The issue may be that the body is still allocating resources toward defense rather than restoration.

The clinical question becomes:

Is the body ready to rebuild?

If the answer is no, then supplementation alone may be poorly tolerated, partially effective, or temporary. The more fundamental task is to reduce adaptive burden and restore recovery capacity.

A recovery-dynamics model of nutrition

A more complete nutritional model should ask four questions:

1. What is depleted?

   Identify nutrient, protein, metabolic, inflammatory, and functional abnormalities.

   
   

2. Why is it depleted?

   Examine intake, absorption, transport, utilization, loss, inflammation, oxidative demand, mitochondrial burden, and exposure load.

   
   

3. Where is the body allocating its resources?

   Determine whether the dominant pattern reflects vital/stress defense, general metabolic reserve compromise, metabolic congestion, or long-term functional depletion.

   
   

4. Can the system convert nutrition into recovery?

   Assess whether the person has enough recovery capacity to use nutrients for repair, muscle rebuilding, immune resolution, redox restoration, and functional improvement.

This is the difference between a replacement model and a recovery-dynamics model.

The replacement model asks:

“What is low, and what supplement raises it?”

The recovery-dynamics model asks:

“What adaptive process is causing this pattern, and how do we restore the system’s ability to recover?”

Why this matters

Nutritional science is moving toward personalization. The recent review on biomarkers for individualized nutritional therapy is an important step in that direction. It recognizes that inflammation, muscle health, endocrine adaptation, catabolism, chronic disease markers, and metabolomics may help predict who benefits from nutritional support.

But personalization needs more than data. It needs interpretation.

Without a framework of finite bioenergetic reserve, stress adaptation, ERM, bioenergetic constraint, and allostatic triage, clinicians may continue searching for one perfect marker or correcting one abnormal nutrient at a time.

The future of nutritional therapy may depend less on finding a single best biomarker and more on learning how to read biomarker patterns as signs of adaptive state.

The key question is not only:

What is depleted?

It is:

Why is it depleted, what biological priority does it represent, and what must change for the body to recover?

Wunderle, C., Urbach, K., Buchmueller, L., Randegger, S., Kaegi-Braun, N., Laviano, A., van Zanten, A. R. H., Seres, D. S., & Schuetz, P. (2025). Biomarkers for individualized nutritional therapy in disease-related malnutrition: A narrative review. The American Journal of Clinical Nutrition, 122, 671–679. https://doi.org/10.1016/j.ajcnut.2025.07.009