1.4 Introduction

This model aims to explain how a long-term illness could develop when the body slowly loses control over energy production, mineral balance, immune signalling, stress hormones, gut microbes and inflammation. It does not assume there is one single cause. Instead, it describes a situation where many small problems build up over time, then eventually lock together into a self-reinforcing cycle.

The main idea is that the body may become trapped in a “survival mode” that is useful for short-term danger, but damaging if it continues for months or years.

In a healthy body, cells constantly manage several linked systems. They make energy from food, store glucose as glycogen, recycle antioxidants, move minerals into the right places, remove toxic metals and chemical waste, calm inflammation after danger has passed, and switch between stress mode and recovery mode. This model proposes that chronic disease can appear when those systems stop coordinating properly.

One possible starting point is before birth. A baby may inherit some risk from the mother’s biology during pregnancy, including metal exposure, mineral status, immune activation, inflammation, stress hormones or altered glucose handling. In this model, gestational diabetes is not viewed only as “too much sugar”. It may also reflect a problem with how glucose is stored and processed. If the body does not have enough magnesium, phosphate, zinc, selenium, folate, choline or other helper nutrients, it may struggle to turn glucose into glycogen, antioxidants and repair materials. So high blood sugar during pregnancy may sometimes be a sign that the glucose-management system is already under strain.

After birth, the model suggests a slow decline rather than one sudden break. Stress, poor sleep, infections, trauma, insufficient carbohydrate intake, low mineral intake, connective tissue problems, neurodivergent stress load, gut problems or toxin exposure may gradually reduce the body’s ability to adapt. For a long time, the person may still function, but they are functioning with less spare capacity.

A central part of this model is redox balance. Redox is the cell’s system for moving electrons during energy production and antioxidant defence. Two important redox systems are NAD⁺/NADH and NADP⁺/NADPH. These are like rechargeable chemical carriers. NAD⁺ helps cells process fuel and keep mitochondria working. NADPH helps recycle antioxidants such as glutathione. Glutathione is one of the body’s main systems for controlling oxidative stress and handling toxic metals.

If NAD⁺, NADPH and glutathione become weak, several things can happen at once. Energy production becomes less stable. The body becomes worse at clearing chemical waste. Toxic metals may be harder to remove. Essential minerals may be lost or moved into the wrong places. Inflammation becomes harder to switch off. Cells may begin to act as if they are under constant threat.

This is where the model becomes more serious. A major immune event may push the system past a threshold. This could be an infection, immune flare, surgery, pregnancy, overexertion, heat stress, toxin exposure, severe sleep loss, emotional trauma or another strong biological stressor. The immune system may release inflammatory signals such as TNF-alpha, IL-1beta, IL-6, IL-10 and IL-22. These signals can increase hepcidin, a hormone that controls iron movement.

Hepcidin is important because it changes how the body moves metals. It can reduce iron export from cells and alter mineral transport through systems such as ferroportin and DMT1. In simple terms, inflammation can cause metals and minerals to be moved out of the blood and into organs such as the liver, spleen, kidneys, immune cells and possibly the brain. This means blood tests may show low minerals, while tissues may still be overloaded or misallocated. The issue is not just deficiency or toxicity. It is poor distribution.

Once this redistribution happens, the body may struggle to maintain basic energy chemistry. Glycogen storage may fall. Glycolysis, the first stage of glucose breakdown, may become unstable. The mitochondria may struggle to process fuel through the TCA cycle and electron transport chain. NAD⁺ may become harder to regenerate. NADPH may become less available for antioxidant defence. ATP, the cell’s main energy molecule, may become harder to use properly.

At the same time, ATP can become a danger signal outside cells. Inside cells, ATP is useful energy. Outside cells, ATP often tells the immune system that tissue is stressed or damaged. This is called extracellular ATP signalling. Normally, extracellular ATP is quickly broken down into ADP, AMP, adenosine and inosine, which can help calm inflammation and support recovery. But in this model, that calming sequence may become impaired.

The result is a split: cells may have too little usable energy inside, while too much danger signalling happens outside. Extracellular ATP can activate receptors on mast cells, immune cells, nerves, blood vessels, gut lining cells, skin cells and brain support cells. This can increase inflammation, pain signalling, mast-cell activation, oxidative stress, cytokine release and “cell danger” signalling. Instead of resolving the problem, the signal keeps repeating.

The gut microbiome may then adapt to this stressed environment. If the body is stuck in sympathetic overdrive, with low oxygen in tissues, poor gut movement, low bile flow, weak immunity and unstable glucose storage, some microbes may shift toward fermentation. This may increase ethanol, acetaldehyde, D-lactate, hydrogen sulphide, ammonia and other microbial products. These may be useful in small amounts or short bursts, but harmful if produced chronically.

Acetaldehyde is especially important in this model. It is a reactive chemical produced from alcohol metabolism and by some microbes. The body normally clears it using aldehyde dehydrogenase enzymes, often shortened to ALDH. These enzymes require good NAD⁺ redox. If NAD⁺ is low or poorly recycled, acetaldehyde clearance may fall. But acetaldehyde itself can further damage redox balance. This creates a loop: poor NAD⁺ makes acetaldehyde harder to clear, and acetaldehyde makes NAD⁺ problems worse.

Acetaldehyde may also interfere with nutrient function. It may reduce zinc availability, disturb magnesium-dependent enzymes, form adducts with thiamine, impair active vitamin B6 handling, affect riboflavin conversion into FMN and FAD, disturb folate and B12 metabolism, lower SAMe, affect retinoic acid signalling, impair CoQ10 production and worsen BH4 oxidation. This could create a “functional deficiency” state. The nutrient may be present in the diet or even appear normal in blood, but may not work properly inside cells.

This connects to histamine. Histamine is not only involved in allergies. It also affects blood vessels, the gut, the brain, immune cells and energy metabolism. In this model, histamine may rise for two reasons: mast cells release more of it, and the body clears it more poorly. Gut barrier damage, antigen exposure, extracellular ATP, oxidative stress and inflammation may trigger mast cells. At the same time, acetaldehyde, low zinc and impaired ALDH or DAO activity may reduce histamine breakdown.

High histamine can then worsen the energy problem. In the liver, histamine signalling may promote glycogen breakdown, reducing stored glucose. This can contribute to blood sugar instability, adrenaline surges, POTS-like symptoms and post-exertional malaise. Histamine may also increase sensitivity to beta-adrenergic signalling, meaning the body reacts more strongly to stress hormones such as adrenaline. Exercise, which normally helps adaptation, may then trigger an exaggerated histamine and inflammatory response.

Another important loop involves nitric oxide and BH4. BH4 helps enzymes make nitric oxide properly. Nitric oxide helps blood vessels relax and supports healthy circulation. If oxidative stress damages BH4, nitric oxide production may become uncoupled, meaning the system produces more superoxide instead. Nitric oxide and superoxide can combine to form peroxynitrite, a damaging reactive molecule. Peroxynitrite may inhibit mitochondrial complex I, making NAD⁺/NADH redox worse. This links oxidative stress, poor blood flow, mitochondrial inhibition and acetaldehyde clearance into one cycle.

As these loops build, the nervous system may shift into sympathetic dominance. The sympathetic nervous system is the “fight or flight” side of the autonomic nervous system. At first, this is protective. It raises alertness, mobilises glucose, supports blood pressure and keeps the person functioning. But if the body cannot restore glycogen, clear glutamate, regenerate NAD⁺, calm extracellular ATP signalling or return to parasympathetic recovery, the stress response becomes maladaptive.

This may create a situation where the body keeps trying to mobilise energy, but cannot store or use that energy properly. Adrenaline, cAMP-PKA signalling, calcium stress, glutamate release, histamine, extracellular ATP and inflammatory cytokines may all amplify each other. The person is biologically pushed to “keep going”, while the recovery systems needed to repair the damage are underpowered.

Connective tissue may also be part of the model, not just a side issue. Collagen production depends on oxygen, iron, vitamin C, copper, silica, glycine, proline, lysine, ATP, redox balance and enzymes such as prolyl hydroxylases. If the body has acidaemia, lactate buildup, hypoxia signalling, oxidative stress, low minerals, poor NADPH repair and chronic inflammation, collagen maintenance may suffer. This could contribute to hEDS-like or vEDS-like features, gut barrier weakness, unstable blood vessels, poor lymph flow, pain, joint instability and higher sensitivity to mechanical stress. Mechanical stress can then release more extracellular ATP and activate mast cells, feeding back into the same cycle.

Over time, the immune system may become both overactive and ineffective. It may produce inflammation, but fail to clear pathogens properly. Poor sleep, low ATP, mineral misallocation, cortisol dysregulation, weak interferon responses and poor nutrient activation may allow viral, bacterial, fungal or other reservoirs to persist. These reservoirs can then keep triggering cytokines, hepcidin, mast cells, extracellular ATP and oxidative stress.

This is why the “what came first?” question becomes less useful in established disease. Early on, the main trigger might have been infection, toxic metals, poor mineral status, pregnancy, trauma, connective tissue fragility, gut dysbiosis, neurodevelopmental stress, histamine intolerance or immune activation. But later, all of these can become connected.

Acidaemia worsens mineral wasting. Mineral wasting worsens ATP chemistry. Poor ATP chemistry weakens glutathione. Low glutathione worsens metal retention. Metal retention worsens mitochondrial redox. Poor redox worsens acetaldehyde clearance. Acetaldehyde worsens histamine clearance. Histamine worsens glycogen instability. Low glycogen worsens adrenaline surges. Adrenaline increases extracellular ATP release. Extracellular ATP sustains inflammation. Inflammation increases hepcidin. Hepcidin worsens metal redistribution. The cycle continues.

The persistence problem is therefore different from a simple lack of vitamins or calories. Vitamins and macronutrients can change fairly quickly. Minerals and metals behave differently. They are stored, transported, locked away, released and redistributed by the liver, kidneys, gut, immune system, mitochondria, glutathione system and inflammatory signals. Once this system is disturbed, it may become harder to get essential minerals into the right places and toxic metals out of the wrong places.

In this model, chronic disease is maintained by a locked pattern: low functional minerals, poor ATP chemistry, weak NAD⁺ and NADPH redox, low glutathione capacity, metal misallocation, acetaldehyde burden, histamine excess, extracellular ATP danger signalling, sympathetic overdrive, glutamate elevation, connective tissue instability, microbiome fermentation, immune weakness and repeated inflammatory triggering.

The treatment implication is that fixing one input may not be enough. Adding one vitamin, one mineral, one antimicrobial, one anti-inflammatory or one diet change may help briefly, but may fail if the wider system remains locked. The goal would be to restore coordination: improve mineral transport, rebuild glutathione, restore NAD⁺ and NADPH balance, reduce acetaldehyde and peroxynitrite stress, improve glycogen storage, calm histamine signalling, reduce excessive extracellular ATP danger signalling, restore adenosine and inosine recovery pathways, reduce maladaptive sympathetic drive, support parasympathetic metabolism, stabilise collagen repair and gradually shift the microbiome away from harmful fermentation.

The core claim is not that the body is permanently broken. It is that the body may become trapped in a defensive state that was originally meant to protect it. Over time, that protective state becomes self-sustaining and harmful. Recovery would require carefully interrupting the loops that keep the mineral, redox, immune, histamine, purine, microbiome and nervous-system problems locked together.

One of the challenges in addressing this condition is its cyclic nature - symptoms often improve and worsen in waves. This pattern, combined with inhibited nutrient absorption in the small intestine, makes it extremely difficult to correct mineral deficiencies through diet or oral supplements alone. Research shows that homeostasis for at least 12 minerals / metals may be affected at various times, depending on the state of inflammation.

During chronic inflammation, accurately measuring systemic mineral levels becomes very difficult, because inflammatory signalling changes how minerals move across cell membranes throughout different tissues in the body. Some tissues will store higher amounts of minerals, eg. brain, liver and kidneys, while other tissues will be deficient. Measuring mineral status via serum or red blood cells in this state becomes highly problematic.

Recent studies have uncovered that disruption of key immune regulators, along with ongoing inflammation involving a hormone called hepcidin, disturbs the body's balance of many biologically essential minerals and also heavy metals. These minerals rely on shared transportation systems in our cells called divalent metal transporter 1 and ferroportin. When the mineral + metal status is disrupted, it creates a cascade of additional problems throughout the body.

In conditions such as ME/CFS, long COVID and post vaccine syndrome, the body’s capacity for cellular energy production is undermined. The underlying problem involves mitochondrial dysfunction, whether due to persistent infection, immune activation, resource insufficiency or accumulated tissue damage. When the mitochondria falter, cells are forced to rely more heavily on glycolysis for energy. This shift leads to chronic lactic acid accumulation and a persistent decrease in blood pH.

In response to ongoing metabolic stress and the resulting acidosis, the body triggers a cascade of immune and neuroendocrine signals. The immune system releases inflammatory cytokines, such as IL-6 and TNF-alpha, which then drive the production of hepcidin by the liver. Hepcidin, a key regulator of mineral and metals metabolism, acts on the gut to limit the absorption of iron and related metals by downregulating importers such as DMT1 and exporters such as ferroportin. As a result, the passage of iron and other divalent metals from the diet into the circulation is reduced, and minerals + metals already in the bloodstream become sequestered inside tissues such as the kidneys, liver, spleen, and brain. Where glutathione synthesis is impaired, these heavy metals may accumulate.

This process is initially a protective strategy. By limiting the availability of key minerals, the body restricts resources that pathogens require to thrive. However, in the context of chronic illness where the original threat is not eliminated, this same mechanism persists far beyond its useful window. Over time, a paradox emerges. Blood tests often show low levels of circulating iron, phosphate, and other minerals, while specific tissue stores may remain normal or even elevated. Attempts to supplement minerals can be ineffective, as the transport machinery that moves these nutrients to where they are needed remains switched off or actively reversed.