Anyone who has experience with ME/CFS-like conditions is deeply familiar with the daily challenge and risks associated with "crashing”, technically called Post Exertional Malaise (PEM).
In contemporary guidelines for diagnosing ME/CFS, PEM is now the key symptom enabling diagnosis, which - in the absence of much discussion about biomarkers, supports or interventions - can give us the mistaken assumption that it is a somewhat designed-in feature with inalterable risks (despite our experience of it being dynamic, changing every day).
PEM typically results in fatigue / malaise, flu-like symptoms and quite frequently - tinnitus, joint laxity and/or pain.
Severe patients often recall how a particular incident of PEM decreased their baseline, or persisted for days / weeks / months. The very real trauma associated with this loss of baseline can additionally contribute to sympathetic overdrive and liver glycogen depletion, perpetuating a loop / trap of these symptoms, without "trauma" having been the origin.
A more complete hypothesis surrounding the mechanisms involved in PEM is important and described in the upcoming paper. However the work-in-progress diagrams are available on the Disease Model page (see figure 9, figure 12, figure 18 and "2.2.6 Cortisol, limbic system, glycogen and IFN-γ" for key influences affecting glycogen homeostasis and mineral status.)
Some highlights from this work describe oxidative stress and (liver) glycogen depletion as the two major variables driving PEM.
Zinc is a cofactor for over 300 enzymes, including those responsible for
metabolising lactate and detoxifying aldehydes (including from
pathogens). Zinc is certainly not the only mineral deficiency involved, but plays a central role in a major self-perpetuating loop that leads to these crashes. "Lactic" acidaemia, which lowers arterial and venous pH, weakens the binding of zinc to albumin, thereby causing the kidneys to accelerate the excretion of zinc and electrolytes in urine. The same acidaemia that causes zinc loss also forces the kidneys to dump phosphate, magnesium, calcium, sodium, and potassium. Because these are required for normal mitochondrial metabolism, glycolysis and coenzyme synthesis, their depletion directly undermines energy production, causes the lactate threshold to lower and the energy crisis to deepen with each episode of acidaemia.
Separately, another branch of this cascade which elevates specific cytokines, further elevates hepcidin, inhibiting Divalent Metal Transporter 1 and Ferroportin - functionally blocking absorption and distribution of at least 11 metals throughout the body.
For example, a deficiency in manganese can significantly impacts hepatic gluconeogenesis (the creation of new glucose) at pyruvate carboxylase, which is a critical factor in preventing the "crash" associated with PEM, as well as post-prandial brain-fog, fatigue.
Similarly, low iron, selenium, iodine and/or calcium availability can affect thyroid hormone synthesis, creating an almost-identical outcome for this part of the metabolism.
Oxidative stress created during exertion, in part caused by insufficient enzymatic metabolism of reactive oxygen species by metal-dependent enzymes like CuZnSOD, MnSOD, glutathione peroxidase + glutathione reductase, catalase consumes excessive Vitamin C and BH4, further disrupting energy pathways and neurotransmitter balance.
Therefore, to prevent PEM, one must not only "pace" mitochondrial metabolism, to appropriate levels of eg. (immune) activity, but also correct resource insufficiencies affecting your biochemistry - maintain levels of glycogen, electrolytes, minerals, and active forms of B vitamins simultaneously. The threshold before encountering PEM is progressively increased / reversed by supplying precision support to these underlying mechanisms. In many cases, this must be achieved by non-oral routes, as the inflammatory cascade blocks normal dietary uptake.
Pacing as only part of the road to recovery
When patients are not informed of these dynamic processes affecting PEM, "pacing" becomes reduced to a management or behaviour strategy, self-management becomes burdonsome, and can be psychologised by care teams, if residually impacted by the logic of Graded Exercise Therapy (GET). However, the second risk in managing PEM, once staging targeted nutritional interventions towards slow repair, is the risk of muscle activity staying below baseline. This needs to be carefully explained because it is not advocating a return to the GET approach (which was based on a false theory of muscle conditioning/deconditioning, whilst ignoring the specific role of pathogens, deficiencies and neuro-immune function affecting capacity otherwise).
The key difference in the disease modelling and protocol here is the recognition of the role of muscle activity in directly promoting the activity of Interferon-gamma (IFN-γ), which the model identifies as a primary tool used by the innate immune system against microbial challenges. Physical activity, along with heat and sex hormones, helps shift the immune system toward this IFN-γ response, which is necessary for tissue adaptations and long-term resilience. Interferon-gamma (IFN-γ) drives the TCA cycle flux, which generates the NADH required to replenish the mitochondrial NADPH pool. This surplus of NADPH acts as a critical reductive currency that powers enzymes like NADPH oxidase (NOX) and nitric oxide synthase (NOS) to produce the reactive oxygen species (ROS) necessary to oxidise and kill pathogens hidden in biofilms.
Furthermore, muscle contractions are the primary driver of lymphatic circulation, ensuring the effective excretion of metabolic waste, and returning extracellular fluids to the bloodstream to prevent blockages that lead to localised hypoxia and lactic acidemia. (This is why manual lymphatic work is even more important when physical exertion is restricted or limited, and on non-exercise days).
While physical exertion promotes essential processes like hormone synthesis and methylation, it must be carefully balanced through "pacing" to avoid over-exertion that triggers periods of lactic acidemia, crippling the enzymes needed for detoxification and energy production.
Consequently, an optimal recovery strategy involves understanding biomarkers, and testing the appropriate upper threshold for activity each day to maintain immune resilience, while ensuring the recovery window remains short and does not provoke an extended period of anaerobic metabolism.
Acidaemia: a key influence in disease progression
Pacing is intended to limit a biochemical loop in which exertion-driven lactic acidaemia and microbiome-derived acetaldehyde combine to accelerate renal and sweat zinc, phosphate, calcium, magnesium, sodium, potassium and other mineral losses and, in turn, deepen the very metabolic defects that provoke symptom flare-ups.
In unstressed adults the kidney excretes roughly 0.02–0.97 mg zinc per 24 h, a volume-dependent trickle that represents a minor fraction of total turnover. A sweat concentration of about 0.5 mg L⁻¹ means two litres of perspiration add ≈1 mg to that baseline. Neither figure on its own threatens balance, but both are highly sensitive to pH and albumin status.
Low arterial or venous pH weakens the high-affinity zinc site on albumin; the drop in binding increases the freely filterable fraction and raises renal clearance in proportion to the acidaemia. In diabetic ketoacidosis (our best human analogue for fermentation-related lactic acidaemia) 24-h urinary zinc typically doubles to about 1 mg and can reach 2–3 mg when urine flow exceeds 3L. Rat studies in ammonium-chloride acidosis show a similar two-fold rise, confirming that pH itself, and not only glycosuria, drives the leak. When mitochondrial impairments push the exercise lactate below pH 7.30, the same renal multiplier is expected in ME/CFS.
Acetaldehyde supplies a second driver. Aldehydes oxidise cysteine thiolates in metallothionein, liberating bound Zn²⁺ and creating a transient cytosolic zinc wave; the displaced ions must then be buffered in plasma, mainly by albumin and, ultimately, by renal clearance.
As gut ethanol is oxidised to acetaldehyde before significant systemic absorption, EtG and other sobriety markers are often negative, yet aldehyde exposure and zinc displacement are continuous. However, Mosaic DX's Toxdetect panel contains 2-Hydroxyethyl Mercapturic Acid (HEMA), which is able to capture acetaldehyde burden.
1. Low pH and acetaldehyde lower albumin affinity, increasing the freely filterable fraction of divalent cations.
2. Acidification and osmotic load inhibit ZIP/ZnT, TRPM6/7 and other re-uptake transporters.
3. Bone buffering dissolves hydroxy-apatite, providing Ca²⁺, Mg²⁺, Zn²⁺ and phosphate that are cleared in the same urine.
4. The loss of Zn further affects lactate dehydrogenase, aldehyde dehydrogenase, prolyl hydroxylase, superoxide dismutase and carbonic anhydrase, worsening aldehyde and lactate accumulation, oxidative stress and buffering capacity, so excretion of every mineral above is amplified again.
Zinc loss is a significant problem. More than 300 enzymes use zinc as a structural or catalytic co-factor, including carbonic anhydrase, aldehyde dehydrogenase, prolyl hydroxylase, Cu/Zn-superoxide dismutase, alkaline phosphatase, RNA and DNA polymerases and multiple DNA repair endonucleases. Figure 7 on the Disease Model page highlights some of the key enzymes relative to the cascade. Falling zinc therefore slows aldehyde dehydrogenase, prolongs aldehyde residence (Vitamin B6, Vitamin A, neurotransmitter metabolites, histamine, etc), weakens carbonic-anhydrase-mediated bicarbonate buffering and blunts superoxide dismutase activity, tightening oxidative and acid-base stress.
The result is a feed-forward loop - lower zinc reduces lactate handling and aldehyde detoxification, pH and acetaldehyde both rise, albumin binding falls further and renal clearance accelerates again.
For pacing the practical target is to keep lactate levels appropriate, venous pH ≥7.30 and sweat volumes modest. Short activity bursts with generous rest, cool environments, avoidance of febrile triggers and rapid rehydration all reduce the renal multiplier and the sweat term.
Elemental zinc intake should routinely exceed 30 mg per day and be coupled with copper and mineral testing to avoid secondary deficiency. Spot or 24h urine zinc above ~1 mg, rising 24h urine lactate or a downward trend in serum albumin signal that either exertion must be cut or supplementation increased.
Out of range lactic acid, oxalic acid and phosphoric acid markers in the OAT are useful indicators for mitochondrial dysfunction and lactic acidaemia.
Phosphorus and sulfur markers on Oligoscan are useful LAGGING indicators for this cascade, also. Where low, and where dietary sufficiency / supplementation is being correctly managed, this can indicate excess exertion, relative to metabolic capacity / lactate threshold. Hypoxia, septicaemia and blood-flow issues should be further explored and excluded.
LDH isoenzymes can be very useful, however also confounded by the zinc and NAD+ status.
Wearable lactate meters will be available in coming months / years.
Left unchecked, daily combined losses in this phenotype reach 2–4 mg, three to six times the obligatory renal flux and is sufficient to disable key zinc enzymes within weeks, creating a spiral progression of metabolic impairments.
NADPH: a reductive "currency", powered by TCA cycle flux
One of the primary tools the innate immune system can use against microbial challenges is creating reactive oxygen species (ROS) to oxidise these pathogens. IFN-γ partially inhibits Complex I, which means that NADH generated by the TCA cycle can be diverted towards elevating NADPH, also powering NADPH oxidase (NOX) and nitric oxide synthase (NOS), which then (like xanthine oxidase, which uses NAD+ instead) create reactive oxygen species to oxidise pathogens, potentially damaging your cells in the process.
Excess NADPH / low NADP with elevated NADH / low NAD+ can be observed / inferred by elevated cholesterols, impaired glucose metabolism, elevated cortisol / inverted diurnal release profile, low aldosterone, low testosterone (often with elevated DHT), low BH4, impaired methylation and various other compensations.
NADPH is a critical cofactor in human metabolism, serving as the primary reductant for antioxidant systems, anabolic pathways, and xenobiotic clearance. While cytosolic sources like glucose-6-phosphate dehydrogenase (G6PD) are well known, a large portion of NADPH - especially during periods of stress or high energy demand - is maintained by the mitochondria, specifically through the enzyme NAD(P) transhydrogenase (NADPT).
NADPT is embedded in the inner mitochondrial membrane and uses the proton gradient to transfer reducing power from NADH to NADP⁺, producing NADPH:
NADH + NADP⁺ + H⁺ → NAD⁺ + NADPH
This links mitochondrial NADH levels - which rise with increased TCA cycle activity - to the regeneration of mitochondrial NADPH.
During exertion/exercise, immune activation, or inflammatory adaptation, metabolic flux through the TCA cycle increases, producing more NADH. As long as the mitochondrial membrane potential (Δψm) remains intact, this NADH surplus feeds directly into NADPT, increasing mitochondrial NADPH availability. The result is enhanced capacity for antioxidant defence (via glutathione and thioredoxin systems), and support for NADPH-dependent biosynthesis, including steroid hormones, proline, and coenzyme Q.
Interestingly, partial inhibition of Complex I, whether through physiological stressors like interferon-gamma (IFN-γ) - used by the body both in immune defence and as a signalling molecule during muscle adaptation - or low-grade mitochondrial oxidative stress, can shift the system into a transiently favourable state. In this “grey zone”, NADH accumulates upstream of Complex I, fuelling NADPT activity more aggressively. As long as the respiratory chain isn’t fully impaired and Δψm is preserved, this can elevate the mitochondrial NADPH pool, supporting redox balance and tissue resilience. This may partly explain the hormetic benefits of controlled stress exposures such as fasting, exercise, or polyphenol intake.
However, this compensatory state is fragile. If Complex I is significantly inhibited - by toxins, sustained inflammation, infection, or mitochondrial dysfunction - the proton gradient begins to collapse. NADPT can no longer function effectively, and NADPH regeneration fails despite high NADH availability. The result is impaired antioxidant defence, loss of redox control, and metabolic vulnerability.
This interplay - between NADH accumulation, proton gradient integrity, and NADPH generation - reveals how mitochondrial function dynamically regulates the redox economy of the cell, determining whether the system bends toward adaptation or collapse.
NADPH functions as a central reducing currency in human metabolism, and the enzymes that consume it fall broadly into two major functional clusters: biosynthesis and innate immune response / detoxification.
On the biosynthetic side, NADPH is used to support a wide range of anabolic processes. Within the mitochondria, endoplasmic reticulum, and peroxisomes, NADPH is required for building complex molecules including cholesterol, steroid hormones, and ubiquinone (CoQ10). It also plays key roles in amino acid interconversion pathways (e.g. proline, ornithine) for collagen synthesis, for methylation and in maintaining cofactor pools such as tetrahydrobiopterin (BH₄) and tetrahydrofolate (THF). Many of these reactions involve reductive steps that cannot proceed without a steady supply of NADPH, especially in pathways with high flux during cell growth, repair, or hormone synthesis.
By contrast, the cytosolic and membrane-associated NADPH-consuming enzymes are primarily involved in defensive or detoxification roles. These include enzymes like NADPH oxidases (NOX), inducible nitric oxide synthase (iNOS/NOS2), and cytochrome P450 reductase (POR), which feed reducing power into systems that produce reactive oxygen and nitrogen species. These reactive molecules play essential roles in microbial killing, xenobiotic metabolism, and immune signalling. In parallel, NADPH also fuels antioxidant and damage-mitigation systems, including the glutathione reductase and thioredoxin reductase pathways, as well as aldo-keto and carbonyl reductases that detoxify lipid peroxidation products and reactive carbonyl species.
Together, these two clusters reflect the role of exertion / TCA cycle flux → NADPH in human physiology - enabling synthesis and repair on one hand, and powering immune defence and redox control on the other. The balance between these uses is tightly regulated, and disruptions-such as oxidative stress, chronic inflammation, or metabolic imbalance-can deplete NADPH reserves, impacting both clusters simultaneously.
For optimal immune response and hormones, “pacing” should always be attempted - testing the appropriate upper threshold for activity, each day, unless that threshold has been exceeded already. Over sufficient time, inactivity leads to immune insufficiency, which is wholly undesirable, as the immune response is pivotal for maintaining resilience against pathogens.
The combination of supplements here should help improve the exertion threshold and buffer against “crashing”. However, you may have already noticed that fungal “die-off” symptoms share some common features with PEM and crashing, as does any immune activity.
(Acetaldehyde ->) histamine is another significant influence, as exertion uses histamine signalling to control glycogen homeostasis in the muscles and liver. This will add some challenges for identifying your upper limits for exertion / glycogen synthesis rate.
(Methylation | glycine recycling ->) (glutathione peroxidase +) glutathione reductase activity provides the cytosolic NADPH redox partnership to G6PD and 6PDG activity in the Pentose Phosphate Pathway. When impaired, this can be a cause of dysregulation for PRPP + R1P synthesis, required for uridine triphosphate -> glycogen synthesis, inosine synthesis and NAD+ synthesis pathways. Certain heavy metals can dramatically impair selenium binding with glutathione peroxidase and its activity while others can impair glutathione reductase activity. In this way, impaired methylation, low glycine or heavy metal toxicity can impair glycogen synthesis rates and cause a lowered PEM threshold.
(You can find more on this in 2.2.6 Cortisol, limbic system, glycogen and IFN-γ.)
Note the upper limit for exertion will be artificially reduced when IFN-γ is elevated and Complex I is inhibited, during any intense immune response. Increasing temperature elevates IFN-γ levels potentially ten-fold. Spirulina, schisandra and curcumin modify this pathway, favourably, by inhibiting NOX.
Proceed carefully. This approach requires edging the upper threshold of your daily baseline with a certain amount of patience and courage, assuming that precision nutritional supports and biomarker literacy make a very real difference to risks of PEM, and that results will come in a non-linear fashion.
Increased baseline can noticeably diminish intracellular pathogen reserves (producing many other benefits to cognitive function etc). As long as your recovery window is short and you're not experiencing extended periods of lactic acid metabolism (see: Figure 12), your exertion falls into the "safe and appropriate" zone and is beneficial towards recovery. If phosphorus (+ sulphur) stalls / gets lower on oligoscans, or oxalate markers increase on OATs, you may need to better support the mitochondrial function, investigate glucose / hypoxia / oxidative stress issues, and/or pace your exertion more.