Clinical Notes

What does HRV actually measure?

Heart rate variability (HRV) measures the variation in time between successive heartbeats — the RR interval. It is not a measure of heart rhythm or heart rate. It is a measure of the autonomic nervous system's ability to adapt in real time.

The autonomic nervous system has two branches: the sympathetic (activation, fight-or-flight) and the parasympathetic (recovery, rest). High HRV indicates that these systems are in dynamic balance — the body can switch rapidly between activation and recovery depending on what the situation demands. Low HRV indicates that the sympathetic system dominates chronically — the body is locked in an activation state regardless of environmental demands.

Why standard HRV interpretation misses what drives low values

Most people measuring HRV — with a smartwatch or clinical equipment — receive a value without understanding the biological mechanisms that govern it. Low HRV is treated as a symptom to address with sleep, meditation and exercise. That is the wrong starting point.

Low HRV is a biological consequence — not a primary dysfunction. The autonomic nervous system is downregulated by an underlying process. The most common primary drivers we see clinically:

• Intracellular magnesium deficiency — magnesium is critical for vagal tone and parasympathetic function. Serum magnesium levels correlate poorly with intracellular status. CMA analysis reveals deficiency levels that standard blood tests cannot detect.
• Chronic low-grade inflammation — inflammatory cytokines (TNF-α, IL-6, IL-1β) directly inhibit vagal nerve function via central mechanisms. ALCAT-identified food intolerances are a common and underdiagnosed inflammation driver.
• Methylation dysregulation — MTHFR variants and methylation cycle deficiencies affect neurotransmitter synthesis and autonomic regulation. MethylDetox analysis is indicated for persistent low HRV without other explanation.
• Mitochondrial dysfunction — the heart's sinoatrial node requires adequate ATP production for normal rhythm variability. Mitochondrial inefficiency appears in HRV patterns before it presents clinically.
• Gut dysbiosis and leaky gut — the gut-brain axis modulates vagal nerve function directly. Gut microbiome composition measurably affects HRV.

HRV in clinical context — what we actually do

At MediBalans, HRV is never used as an isolated metric. It is one of five primary measures in our autonomic assessment, interpreted against:

• CMA results (intracellular magnesium, CoQ10, B vitamins)
• ALCAT profile (inflammation drivers via immune reactivity)
• MethylDetox panel (autonomic regulatory genes including COMT, MAO-A)
• Gut barrier markers (zonulin, secretory IgA)
• Cortisol diurnal profile (DUTCH panel)

Treatment is directed at the identified primary constraint per the GCR framework — not at the HRV value itself. The goal is for HRV to normalise as a consequence of correcting the underlying biology.

HRV is the thermometer. The temperature tells you something is wrong — not what is wrong. The clinical work begins when you ask why.

Clinical indications for HRV investigation

HRV analysis is indicated when the patient presents with any of the following without adequate explanation from standard tests:

• Chronic fatigue and energy deficit
• Impaired recovery after exercise or stress
• Sleep disturbances with maintained sleep hygiene
• Stress-related cardiovascular symptoms
• Autoimmune conditions with autonomic component
• Palpitations without arrhythmia on ECG
• Functional dyspepsia and IBS with autonomic component

The problem with symptom-based medicine

Conventional medical diagnostics is fundamentally symptom-based: the patient presents with a symptom, the clinician matches it to a diagnosis, treatment is directed at the diagnosis. For acute conditions and single organ system disease, this works well.

For complex chronic disease — IBS, chronic fatigue, autoimmunity, fibromyalgia, recurrent infections — it systematically fails. Patients return with unchanged or worsening symptoms despite adequate treatment of the primary diagnosis. The explanation is almost always the same: treatment has targeted a compensation, not the primary biological constraint.

Global Constraint Rule — the definition

Global Constraint Rule (GCR) is a systems biology principle describing how biological systems handle limitations:

Biological systems always adapt to their most limiting factor — not their most obvious one. Identifying and correcting the primary constraint is more effective than treating the adaptive compensations it has generated.

In practice, this means that a biological system's visible dysfunction is rarely caused directly by the primary constraint — it is often a secondary compensation the system has generated to handle a limitation elsewhere in the network.

A clinical example

Patient presents with IBS, chronic fatigue and recurrent urinary tract infections. Standard investigation shows nothing pathological. Treatment of IBS symptoms provides temporary relief but no lasting result.

GCR analysis of the biological profile identifies:

• Primary constraint: Severe intracellular zinc deficiency (verified via CMA) impairing gut barrier integrity and immune function
• Secondary compensation: Immune reactivity against 47 foods (ALCAT) — the immune system is hypersensitised in response to leaky gut
• Tertiary effect: Autonomic dysregulation (low HRV) in response to chronic inflammatory load

Treating IBS symptoms (tertiary effect) or even elimination protocols based on ALCAT (secondary compensation) without correcting the intracellular zinc deficiency produces temporary improvement. As soon as exposure resumes, reactivity returns — because the zinc deficiency is still there.

Correct GCR protocol: intracellular zinc repletion (IV if severe deficiency) → gut mucosal restoration → gradual food reintroduction. Immune reactivity decreases on its own as barrier function is restored.

GCR in diagnostic practice

The GCR framework requires multi-omics data for correct application. A single test — however good — cannot identify the primary constraint in a complex chronic condition. It requires:

• Cellular level: CMA (55 intracellular micronutrients) to identify metabolic bottlenecks
• Immunological level: ALCAT to map immune reactivity patterns and identify secondary compensations
• Genetic level: MethylDetox to understand genetic constraints affecting the methylation cycle
• Microbiome level: GI Effects for the gut microbiome's role in gut barrier function and immune modulation
• Autonomic level: HRV to quantify the systemic effect of the biological constraints

The data points converge toward a primary constraint profile. The protocol is designed to address constraints in the right order — not simultaneously, which is rarely effective.

Why doesn't chronological age tell you what matters clinically?

Two 50-year-old patients with identical chronological age can have fundamentally different biological profiles — one with a cellular ageing marker profile corresponding to a 38-year-old, the other with a marker profile corresponding to 64. That is the difference between a body ageing well and a body ageing too fast.

Chronological age is an administrative metric. Biological age is a clinical metric. The decisive question is not how long you have lived — it is how your cells are ageing right now, and whether the process can be slowed or reversed.

The problem with existing biological age methods

The most common biological age markers today — telomere length, epigenetic clocks (Horvath, Hannum, PhenoAge) — have clinical limitations:

• Telomere length: Measures accumulated cellular stress but not current biological function. Correlates poorly with clinical outcome at the individual level.
• DNA methylation clocks: Measure epigenetic changes but do not capture translational discrepancy — that is, the gap between what the genes say and what the cells actually produce.
• Inflammation markers (GrimAge): Better clinical prediction but still a one-dimensional approximation of a multidimensional process.

None of these methods measure the critical step in cellular ageing biology: the translational gap — the discrepancy between gene expression (transcriptome) and protein production (proteome).

BioAge™ — the methodology

MediBalans BioAge™ combines three analytical layers into a converged biological age measurement:

Layer 1: RNA transcriptome analysis

Via the Dante Labs platform, 42,000 RNA biomarkers are analysed representing the entire active gene expression. The transcriptome reflects the cell's current biological state — not just genetic potential, but what the genes are actually doing right now. We compare the expression profile against a longevity reference panel derived from well-characterised ageing cohorts.

Layer 2: Proteomic profiling

The protein production profile is analysed separately. The protein is the functional unit — it is proteins that perform cellular work, not genes. A gene can be active (transcribed) without producing normal protein levels, and vice versa.

Layer 3: Translational gap analysis (patented)

The patented step. We systematically measure the discrepancy between transcriptome and proteome — the translational gap. Normally ageing biology shows a predictable gap. Accelerated ageing shows a deviant gap pattern in specific biological domains.

The gap pattern identifies where in the cell's machinery the ageing process is most active — mitochondrial function, protein folding, DNA repair, inflammation signalling — which enables precision-targeted interventions.

What the result reveals — and what we do with it

The BioAge™ analysis delivers a biological age measurement with specified deviation patterns per biological domain. It is not a number — it is a biological map.

If the translational gap analysis identifies deviation in the mitochondrial domain, the protocol is directed at mitochondrial support: CoQ10 levels via CMA, NAD+ supplementation, HRV-based exercise optimisation. If the deviation is primarily in inflammation signalling, the protocol is directed at immune modulation and inflammation reduction.

Follow-up measurement occurs after 3 months. Biological ageing process is measurably reversible — we have seen biological age reduction of 3–7 years in the cohort after 6 months of targeted intervention.

IBS is multifactorial. It begins upstream — antibiotics, processed food and other insults disrupt the microbiome; the innate immune system reacts to food and microbial antigens, driving inflammation; the gut barrier becomes permeable; and the gut's mitochondria take the hit. Mitochondrial dysfunction is the downstream consequence, not the cause. Genetics and epigenetics set susceptibility throughout.

Why the IBS diagnosis explains so little

IBS is a symptom-based diagnosis. It says the gut is behaving abnormally — not why. Abdominal pain, bloating, altered bowel habits without structural pathology. The diagnosis excludes what it is not. It does not identify what it is.

That is why treatments aimed at symptoms — antispasmodics, laxatives, low-FODMAP diets, motility drugs — give temporary relief for some but rarely a biological resolution. Patients return, because the cascade underneath has not been addressed.

The cascade behind IBS

IBS is best understood not as one defect but as a sequence — each step feeding the next:

• 1 · The trigger and the microbiome. Antibiotics, ultra-processed foods and similar exposures shift the gut microbiome toward dysbiosis — a loss of the balance that normally keeps the immune system calm.
• 2 · Innate immune activation. The innate immune system reacts to food and microbial antigens, releasing interleukins, cytokines and chemokines, generating free radicals and low-grade inflammation. ALCAT is the readout of this immune reactivity.
• 3 · Barrier breakdown — leaky gut. Sustained inflammation degrades the tight junctions between epithelial cells; permeability rises and the barrier begins to leak, letting more antigen through and amplifying the immune response.
• 4 · The mitochondria take the hit. Chronic oxidative and inflammatory load, plus the constant energy cost of repairing a damaged barrier, leaves the gut-lining mitochondria depleted. This is the casualty at the end of the chain — measurable via CMA, worth correcting for symptom relief, but a consequence, not the cause.

The susceptibility layer — genetics and epigenetics, running throughout

Nutrigenetic and epigenetic variation does not sit at one step — it shapes the whole cascade: how reactively the immune system fires, how well detoxification and methylation handle the oxidative load, and how resilient the barrier is. Two people with the same dysbiotic trigger can travel very different distances down the cascade. MethylDetox and whole-genome sequencing map this layer.

How MediBalans investigates IBS

We map the cascade in causal order rather than treating the end-point:

• Microbiome — GI Effects: dysbiosis, barrier markers (zonulin, secretory IgA) and the microbial picture upstream.
• Susceptibility — WGS + MethylDetox: the nutrigenetic and methylation variants that set how strongly each step fires.
• Immune readout — ALCAT: the degree of immune reactivity, and an elimination protocol while the barrier recovers.
• Downstream toll — CMA: the intracellular nutrient and energy status the cascade has depleted — what to correct for symptom relief.

Common questions

What actually causes IBS?

IBS is multifactorial. It develops as a cascade: a disrupted microbiome, an innate immune response to food and microbial antigens, chronic inflammation, and a barrier that becomes permeable. Mitochondrial dysfunction in the gut lining is a downstream consequence of that burden — not the cause. Genetic and epigenetic susceptibility shapes how strongly each step fires.

Is IBS a bowel disease?

IBS is not a structural bowel disease — there is no visible tissue damage. It is a functional condition arising from the interplay of microbiome, immune activation and barrier dysfunction.

What is the role of leaky gut in IBS?

Increased intestinal permeability sits in the middle of the cascade: chronic inflammation degrades the tight junctions, the barrier leaks, more antigen crosses, and the immune response amplifies. It is a step in the chain, not the root.

Is mitochondrial dysfunction the cause of IBS?

No — in this model it is a downstream consequence. The chronic oxidative and inflammatory load, and the energy cost of constant barrier repair, deplete the gut-lining mitochondria. It is measurable and worth correcting for symptom relief, but it is the casualty at the end of the cascade, not the trigger.

What tests are relevant for IBS?

In causal order: GI Effects for the microbiome and barrier markers; WGS and MethylDetox for genetic/epigenetic susceptibility; ALCAT for immune reactivity; and CMA for the downstream intracellular nutrient and energy depletion.

What is post-exertional malaise and why does it happen?

The diagnostic criterion that distinguishes ME/CFS from ordinary fatigue — post-exertional malaise (PEM) — is a direct mitochondrial fingerprint. PEM means that physical or cognitive exertion triggers a crash phase 12–48 hours later that can last days to weeks.

The mechanism is biochemical: during exertion, ATP demand increases dramatically. Mitochondria with impaired capacity cannot meet demand via oxidative phosphorylation and compensate with anaerobic glycolysis — inefficient, fast, and producing lactate as a byproduct. PEM is mitochondrial debt. The body borrows ATP equivalents it doesn't have — and pays interest in the form of days of collapse.

Why the brain is disproportionately affected

The brain constitutes 2% of body weight but consumes 20% of the body's total energy production. Neurons are extremely sensitive to ATP deficiency — they cannot store glycogen and depend on continuous mitochondrial ATP synthesis. Cognitive dysfunction ("brain fog"), light and sound sensitivity, and sleep disturbances are neurological consequences of cellular energy deficit.

This is not psychosomatic. It is neuroenergetic physiology.

What are the primary mitochondrial drivers in ME/CFS?

• Carnitine deficiency: L-carnitine transports long-chain fatty acids into mitochondria for beta-oxidation. Intracellular deficiency — measurable via CMA — blocks fatty acid oxidation and dramatically reduces ATP capacity. One of the most consistently underestimated findings in the fatigue cohort.
• CoQ10 deficiency: As with IBS — CoQ10 is the electron transport chain's key component. Deficiency directly reduces ATP efficiency. Statin treatment reduces CoQ10 synthesis as a side effect and can trigger or worsen chronic fatigue.
• Mitochondrial oxidative stress: Accumulated ROS (reactive oxygen species) damages mitochondrial membranes and DNA. Chronic inflammation — driven by ALCAT reactivity, intestinal permeability, or infection history — is a primary ROS source.
• NAD+ depletion: NAD+ is essential for the Krebs cycle and sirtuin activation. Age, inflammation and chronic stress reduce NAD+ levels. NMN supplementation via NMN+5™ addresses this specifically.
• Thyroid-mitochondrial axis: Thyroid hormones directly regulate mitochondrial biogenesis and respiratory chain protein expression. Subclinical hypothyroidism — with normal TSH but low free T3 — is a frequently overlooked energy constraint.

Long COVID and ME/CFS — the same mitochondrial mechanism

Post-COVID fatigue fulfils ME/CFS criteria in a significant proportion of cases. SARS-CoV-2 causes direct mitochondrial damage via ORF proteins that interfere with complex I in the electron transport chain. The result is identical to ME/CFS: impaired oxidative capacity, PEM, neuroinflammation, and HRV collapse.

This retrospectively confirms the thesis: ME/CFS is not a disease. It is a clinical syndrome that arises when mitochondrial function fails sufficiently — regardless of what caused the failure.

The immune system's energy demands are extreme

Immune activation is one of the body's most energy-demanding processes. An activated T cell increases its metabolic rate 100-fold. Dendritic cells require massive ATP production to process antigen and present it to T cells. Natural killer (NK) cells require adequate mitochondrial function to perform cytotoxicity.

But no immune population is more mitochondrially sensitive than Treg cells. Tregs differ metabolically from conventional T cells: they depend on oxidative phosphorylation rather than glycolysis for their suppressive function. Energy deficiency selectively disables the immunological brake mechanism — while the accelerator remains intact.

Why is the gut barrier central to autoimmune disease?

70% of the immune system resides in the gut — the intestinal lymphoid tissue (GALT). The gut barrier is the primary boundary between external antigen exposure and the immune system's activation state.

Mitochondrial failure in gut epithelium → increased intestinal permeability → continuous low-grade antigen exposure → chronic Treg exhaustion → erosion of self-tolerance. This is not an immune system "mistake." It is an exhausted immune system that has lost the capacity to distinguish self from non-self.

Clinical consequence: most autoimmune patients we see have a strong ALCAT reactivity pattern. That is not the primary constraint — it is a barometer of how long the gut barrier has been leaking.

Methylation biology and autoimmunity

Epigenetic regulation of immune gene expression depends on the methylation cycle. MTHFR variants reduce folate availability for DNA methylation. Undermethylation of immune regulatory genes — including FOXP3, the master regulator of Treg identity — has been documented in multiple autoimmune conditions including SLE, RA and MS.

MethylDetox analysis is therefore not just relevant for fatigue and neuropsychiatry. It is central to understanding the genetic constraint behind autoimmune predisposition.

Vitamin D — mitochondrial immune modulator

Vitamin D is a steroid hormone that directly regulates Treg differentiation via the VDR receptor. Intracellular vitamin D deficiency — most common in northern populations and in Scandinavia for 8 months per year — is one of the most consistently correctable constraints in autoimmune disease.

Important: serum analysis of 25(OH)D3 is insufficient. Intracellular vitamin D status is measured via CMA and can differ markedly from serum — patients with normal serum values can have severe intracellular deficiency in the immune cells that actually need it.

How SARS-CoV-2 damages mitochondria

SARS-CoV-2 encodes ORF3a and ORF9b proteins that directly interfere with mitochondrial function. ORF9b binds to TOM70 — the outer mitochondrial membrane's import receptor — and blocks import of respiratory chain complexes. The result is a direct impairment of complex I activity and reduced ATP production.

The virus also hijacks mitochondrial dynamics: it inhibits fusion and promotes fission, leading to fragmented, dysfunctional mitochondrial networks. Normal cells contain interconnected mitochondrial networks — infected cells have isolated fragments with impaired capacity.

Why do some people not recover from COVID-19?

The majority recover from SARS-CoV-2 with preserved mitochondrial function. A minority — estimated at 10–30% of symptomatic cases — develop Long COVID. Risk factors are well-characterised and biologically coherent:

• Pre-existing mitochondrial reserve deficiency: Patients with subclinical CoQ10, carnitine or B-vitamin deficiency lack the buffer capacity to handle virus-induced mitochondrial damage.
• Methylation defects: MTHFR variants reduce glutathione production — the primary antioxidant buffer against mitochondrial ROS damage. Impaired glutathione status allows oxidative damage to persist post-infection.
• Autoimmune activation: SARS-CoV-2 triggers molecular mimicry against mitochondrial proteins in genetically predisposed individuals. Autoimmune mitochondrial damage persists after the virus is eliminated.

Long COVID and ME/CFS — clinical convergence

Post-COVID syndrome fulfilling ME/CFS criteria is biologically identical to ME/CFS of other aetiology. Same mitochondrial failure, same PEM pattern, same HRV collapse, same CMA profile. This is the strongest retrospective validation of mitochondrial theory of ME/CFS — a global natural study with millions of patients demonstrating that a single mitochondrially toxic agent can induce the condition.

Long COVID is not mysterious. It is documented mitochondrial damage that was not repaired. It is treated the same way as any other mitochondrial dysfunction — systematically, at the cellular level.

MediBalans protocol for Long COVID

Based on the mitochondrial mechanism, priority is given to:

• NAD+ restoration: NMN+5™ (patented formulation) supports NAD+ synthesis and sirtuin activation for mitochondrial biogenesis.
• CoQ10 and carnitine: CMA-guided intravenous correction for confirmed deficiency for rapid mitochondrial support.
• Glutathione therapy: IV glutathione directly reduces mitochondrial oxidative load and supports membrane repair.
• Methylation optimisation: MethylDetox-guided supplementation normalises glutathione production and addresses genetic predisposition to insufficient repair.

Why is glucose not the primary problem in insulin resistance?

Skeletal muscle is the body's primary glucose depot — responsible for 70–80% of insulin-mediated glucose uptake. When mitochondrial oxidation capacity in muscle cells is impaired, glucose cannot be metabolised fast enough. Glucose accumulates intracellularly as lipid intermediates (diacylglycerol, ceramides) that directly inhibit the insulin signalling cascade.

Insulin resistance is the muscle cell's way of saying: I cannot handle more substrate — my power plants are undersized. Glucose stays in the blood not because insulin is weak, but because the destination lacks capacity.

Why metformin works — and what it reveals

Metformin, first-line treatment in type 2 diabetes, acts primarily via AMPK activation in the liver. AMPK is the cell's energy sensor — it activates when the ATP/AMP ratio falls, meaning when cells experience energy deficiency. AMPK activation stimulates mitochondrial biogenesis and increases oxidation capacity.

This is an indirect confirmation of the mechanism: the most successful pharmacological treatment for type 2 diabetes works partly by improving mitochondrial function. Logical consequence: addressing mitochondrial dysfunction directly and causally should produce better results.

What drives mitochondrial dysfunction in metabolic syndrome

• Chronic low-grade inflammation: Adipose tissue in overweight individuals continuously produces pro-inflammatory cytokines (TNF-α, IL-6) that directly inhibit mitochondrial biogenesis via PGC-1α downregulation.
• NAD+ depletion: Chronic glucose excess activates PARP enzymes that consume NAD+ in DNA repair processes. Reduced NAD+ impairs sirtuin activity and mitochondrial quality control.
• Intracellular magnesium deficiency: Magnesium is a cofactor for 300+ enzymatic reactions including pyruvate dehydrogenase — the key enzyme that brings glucose into the Krebs cycle. Magnesium deficiency directly blocks glucose's route to ATP synthesis.
• Methylation defects and one-carbon metabolism: MTHFR variants affect homocysteine metabolism and coenzyme A biosynthesis. Elevated homocysteine is an independent risk factor for mitochondrial damage via increased oxidative stress.

ALCAT and metabolic syndrome — the connection

Food intolerance reactions drive systemic low-grade inflammation via intestinal permeability. Chronic inflammation is one of the strongest drivers of mitochondrial biogenesis inhibition and insulin resistance. It is not uncommon to see dramatic improvement in metabolic markers through ALCAT-based elimination protocols alone — not because the diet changes in caloric or carbohydrate quality terms, but because the chronic inflammation driver is removed.

Popular senolytics and polyphenols are catechol-COMT substrates. In a slow methylariser — especially with MTHFR or low folate/B12 — a high supplemental dose competes for methyl groups. Measure first, individualise.

The longevity molecule and the enzyme it shares a table with

The senolytic favourites quercetin and fisetin, and the green-tea polyphenol EGCG, are catechol-containing flavonoids. They are cleared by the same enzyme that methylates dopamine, noradrenaline, adrenaline and catechol-oestrogens — catechol-O-methyltransferase, COMT.

COMT works by transferring a methyl group from SAM (S-adenosylmethionine) to the catechol structure. Every catechol it handles costs one methyl group — the dopamine you just released under stress, the oestrogen metabolite to be neutralised, and the quercetin capsule.

The mechanism — substrate and competition

Two things happen at once when a high supplemental dose of catechol polyphenols is added:

• They consume SAM. Each O-methylation spends a methyl group from the SAM pool.
• They compete for the enzyme. As COMT substrates they competitively inhibit the clearance of catecholamines and catechol-oestrogens — they stand in the same queue.

Quercetin and fisetin have particularly high COMT affinity; in a pharmacokinetic study they were methylated by COMT in preference to catechins.^[3] The binding strength shows in IC₅₀ data for inhibition of catechol-oestrogen methylation: quercetin 0.9–1.5 µM, fisetin 3.3–4.5 µM, EGCG 0.04–0.07 µM.^[2] A documented downstream consequence: in an animal model a 3% quercetin diet lowered the renal SAM pool by ~25% and nearly doubled SAH^[1] — and SAH itself inhibits methyltransferases.

Who this concerns — the COMT genetics

COMT activity is largely genetically determined. The functional variant rs4680 (Val158Met) sets the speed: Val/Val has three to four times higher activity than Met/Met. Met/Met is the slow COMT profile — less margin when the load rises.

The distribution is population-dependent, but for a patient base of European ancestry the rule of thumb is useful: roughly one in four carries the slow (Met/Met) variant, and about half carry one slow copy (Val/Met, intermediate). In mixed cohorts the Met/Met share runs lower, around 15%.

Amplifying factors

• MTHFR and methylation status. MTHFR variants or low folate/B12 cause undermethylation — less SAM, more SAH. Since SAH inhibits COMT, slow COMT combined with undermethylation is an unfavourable stack.
• Catechol-oestrogen load. Oestrogen metabolites are cleared via the same COMT and compete for the enzyme alongside the polyphenols.

The clinical point — sequence, not abstinence

This is not an argument against polyphenols. Polyphenols in food — tea, berries, olive oil — are beneficial and arrive at doses the system handles. The question is narrower: concentrated high-dose senolytic protocols in someone who is genetically a slow methylariser and possibly undermethylating. Map the methylation system first — folate/B12, homocysteine, COMT and MTHFR genotype — then individualise the polyphenol load.

Common questions

Is quercetin dangerous with slow COMT?

No — the question is dose and sequence, not danger. In a slow methylariser, high supplemental doses compete for COMT and the SAM pool. The answer is to map COMT and MTHFR genotype and methylation status, then individualise the dose.

Should I avoid fisetin and senolytics if I have COMT Met/Met?

Not avoid — sequence. Optimise methylation first (folate/B12, homocysteine), know your genotype, then dose deliberately rather than stacking blind.

Does this affect polyphenols in food, like tea, berries and olive oil?

No. Dietary polyphenols arrive at doses the system handles well and are beneficial. This concerns concentrated high-dose supplements.

How do I know if I have slow COMT?

COMT rs4680 is included in the MethylDetox panel and in whole-genome sequencing, which also shows your MTHFR and other methylation genes.

What is the link between MTHFR and COMT?

MTHFR-driven undermethylation lowers SAM and raises SAH, and SAH inhibits COMT. Slow COMT and undermethylation therefore compound one another. Both are on the MethylDetox panel.

NAD supplements are broken down by methylation — a process that consumes methyl groups and produces homocysteine, a cardiovascular marker. At sensible doses with good methylation, fine. High doses, or a slow methylariser (MTHFR, low folate/B12), can raise homocysteine.

The NAD deficit everyone wants to fill — and the way out of the cell

NAD+ declines with age, and the longevity market fills it with precursors: niacinamide (NAM), nicotinamide riboside (NR) and NMN. The logic is simple — add substrate, raise NAD+. But there is a second half of the equation that is rarely discussed: how the body clears the surplus. The main route out for nicotinamide is methylation, via the enzyme NNMT.

The mechanism — one methyl group per molecule, homocysteine on the side

NNMT transfers a methyl group from SAM to nicotinamide. The result is methylnicotinamide (excreted in urine) and SAH, which is in turn hydrolysed to homocysteine.^[1] Every nicotinamide molecule cleared this way costs one methyl group from the SAM pool and leaves one homocysteine behind — a double outflow. A genome-wide study identified NNMT as one of the key genetic determinants of plasma homocysteine.^[3]

Homocysteine — the cardiovascular link

Elevated homocysteine is an established cardiovascular risk marker, linked to endothelial dysfunction and atherosclerosis. NNMT activity is associated in the literature with atherosclerosis, heart failure and coronary disease, partly via hyperhomocysteinaemia and NAD disturbance.^[4] The key lies in recycling: homocysteine is normally remethylated back to methionine, a process requiring folate (via MTHFR), B12 and B6. It rises most when that recycling capacity is limited.

Who is exposed — dose and methylation capacity

The risk is conditional, not general. Two factors decide:

• Dose and trial length. The human data cited as reassuring come from short phase I trials — NADPARK (NR 1000 mg/day, 30 days, 30 newly diagnosed Parkinson patients) and NR-SAFE (3000 mg/day, 4 weeks, 20 patients). They show methylation balance holds at group level over a month in a largely methyl-replete cohort. But they neither enrolled nor stratified for the variants that make an individual susceptible — MTHFR, MTR, MTRR, AHCY, COMT — and 30 days does not capture cumulative drift over months. Absence of a signal in NADPARK is therefore not evidence of safety in a slow methylariser on a longer protocol.^[2][5] Evidence for actual methyl-group depletion comes from very-high-dose animal models, often with methyl-donor-deficient diets.
• Methylation capacity. MTHFR variants and low folate/B12 limit homocysteine recycling, so the homocysteine NNMT generates accumulates. Undermethylation is the amplifier.

Taken together: a high NAD-precursor load in someone with limited methylation capacity is the situation that deserves attention — not NAD precursors in themselves.

Common questions

Are NAD supplements (NMN/NR) dangerous for the heart?

Not in themselves, but the question is poorly studied for those who are susceptible. The reassuring human data come from short phase I trials (about 30 days) in Parkinson cohorts not stratified for methylation variants such as MTHFR, MTR, MTRR, AHCY or COMT. They say little about a slow methylariser on a long-term protocol, where NNMT-generated homocysteine can accumulate. That is why we measure homocysteine and methylation status rather than assume.

Does niacinamide raise homocysteine?

It can. Niacinamide is methylated by NNMT with SAH, and therefore homocysteine, as a by-product. How much depends on dose and on how well homocysteine is recycled, which is governed by folate, B12 and MTHFR status.

Why does MediBalans give NMN with cofactors instead of NAD alone?

Because the breakdown pathway consumes methyl groups and produces homocysteine. Supplying methyl donors such as TMG, methylfolate and B12 alongside NMN supports that pathway rather than burdening it. Substrate without cofactors is half the measure.

Should I measure anything before taking NAD boosters?

Yes — homocysteine, folate and B12, and ideally MTHFR and other methylation genes. It shows whether your methylation capacity matches the load you plan.

What does MTHFR have to do with NAD supplements?

MTHFR governs the recycling of homocysteine to methionine. A slow variant with low folate limits that recycling, so homocysteine generated when NAD precursors are broken down is cleared less well. MTHFR is on the MethylDetox panel.