2.2.4 The importance of “pacing” or “just enough activity”
Anyone who has experience with ME/CFS is likely to have gained a significant appreciation for the symptoms associated with “crashing” and Post Exertional Malaise (PEM).
A well-earned daily fear that too much activity will “crash” you and leave you with fatigue / malaise, flu-like symptoms and often tinnitus. A further fear that this may persist for days / weeks / months. This perception can contribute to sympathetic overdrive and liver glycogen depletion, perpetuating a loop / trap of these symptoms.
A hypothesis surrounding the mechanisms involved in PEM is being described in the upcoming paper, however the work-in-progress diagrams are available on the Disease Model page.
Unfortunately, due to the trauma of repeatedly experiencing PEM, some people understandably choose to severely limit their activity. This unfortunately has an impact on the capabilities of their immune system to deal with chronic infection.
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.
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 short-circuits push 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. Because 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, MosiacDX'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 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
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 “rotting”, which is wholly undesirable, as the immune response is expected to be insufficient 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.
(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, however the age-old phrase “no pain, no gain” absolutely applies here. 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.