The conventional view that MTHFR variants and folate receptor autoantibodies represent pure dysfunction is increasingly challenged by evidence suggesting these may be adaptive mechanisms that protect against oxidative damage. Research shows that reduced methylation activity—whether from genetic variants, autoantibodies, or methionine restriction—consistently decreases mitochondrial ROS production and extends lifespan across species, while high methylation activity creates an oxidative burden through the SAM-ubiquinone-ROS pathway. Individual variation in “buffer capacity” (primarily glutathione reserves, electrolytes, and antioxidant enzymes) determines who can sustain increased methylation demands and who will experience threshold effects when these reserves deplete. This framework helps explain why some people tolerate methylation support for months before crashing, why pregnancy complications cluster in women with MTHFR variants, and why pushing methylation without addressing oxidative stress can be harmful.
The methylation-oxidative stress relationship represents a fundamental biochemical tradeoff: higher methylation supports biosynthesis and growth but generates damaging reactive oxygen species, while slower methylation reduces cellular capacity but protects against oxidative damage accumulation. Context determines which side of this equation proves beneficial.
The mechanistic foundation: how methylation generates oxidative stress
Methylation activity directly drives mitochondrial ROS production through a well-characterized biochemical pathway. Research published in Nature Communications (2024) identified that the methionine-SAM axis generates reactive oxygen species specifically through ubiquinone (coenzyme Q10) synthesis. Ubiquinone requires three methylation steps for its production and serves as the primary electron carrier in the mitochondrial respiratory chain. More SAM availability means more ubiquinone synthesis, which leads to increased electron transfer and greater electron leakage at Complex I and III—the primary sites of superoxide generation.
When researchers blocked this pathway with antimycin A, they completely prevented SAM-based ROS accumulation, demonstrating the direct causal link. Ubiquinone stands unique as the only electron transport chain carrier requiring methylation for synthesis, creating a direct mechanistic connection between methylation rate and oxidative stress generation.
Methionine restriction studies across multiple species provide compelling evidence for this relationship. Reducing dietary methionine by 40% decreases mitochondrial ROS production at Complex I, lowers oxidative damage to mtDNA and proteins, and extends maximum lifespan by up to 45% in rodents. These effects occur across heart, brain, liver, and kidney mitochondria. The mechanism involves methionine metabolites reacting with Complex I to create radicals or methanethiol, which causes mtROS overproduction. Restricting methionine prevents this thiolization of Complex I, resulting in lower ROS leak and reduced oxidative damage.
Critically, methionine restriction simultaneously decreases DNA methylation by 40% while decreasing mitochondrial ROS and oxidative damage. This contradicts the assumption that hypomethylation is universally harmful, instead suggesting that lower methylation can be protective by reducing the oxidative burden.
MTHFR variants show protective effects through reduced oxidative stress
MTHFR C677T and A1298C variants, present in over 50% of many populations, show surprising protective associations that make sense through an oxidative stress lens. The C677T variant reduces enzyme activity by 35% in heterozygotes and 70% in homozygotes, while A1298C reduces activity by roughly 40% in homozygotes. Rather than being purely detrimental, these variants show context-dependent benefits.
A large case-control study (Nature Scientific Reports, 2016) with over 3,800 participants found that the CT genotype reduced prostate cancer risk by 22% (OR=0.78) while the TT genotype reduced risk by 32% (OR=0.68). The mechanism appears counterintuitive: elevated homocysteine from the variant causes DNA damage, which increases apoptosis in cancer cells, reducing their proliferation. The “dysfunctional” variant provides protection against cancer development.
Similar protective associations appear for colorectal cancer, where MTHFR C677T carriers show decreased risk when folate levels are adequate. The variant allows more 5,10-methyleneTHF to be available for DNA synthesis rather than being converted to 5-methylTHF, preventing uracil misincorporation and improving DNA stability despite reduced methylation capacity.
Most compellingly, the T allele and TT genotype appear significantly more prevalent in people aged 90 and older. A Chinese long-lived cohort study (Lipids in Health and Disease, 2014) found the T allele frequency significantly higher in centenarians compared to younger populations (p=0.001), with the effect particularly pronounced in females. The study authors concluded that “higher prevalence of MTHFR 677 T genotypes…may imply an existence of other protective genotypes.” Additionally, elderly Chinese males with the CT genotype showed better cognitive function than either CC or TT, suggesting an optimal intermediate methylation rate—a classic heterozygote advantage pattern.
The geographic distribution of MTHFR variants provides further evidence of adaptive selection. A study in the Journal of Human Genetics (2012) found an inverse U-shaped relationship between T allele frequency and UV radiation exposure, with UV radiation being a better predictor than latitude or climate. This suggests environmental selection pressure, possibly representing the “white man’s blackness”—a metabolic adaptation that conserves folate in low-UV northern environments where folate degradation from sunlight is less of a concern but dietary availability may be limited.
Folate receptor autoantibodies: when blocking appears protective
Perhaps the most surprising evidence for protective methylation slowdown comes from folate receptor autoantibodies, where blocking-type antibodies paradoxically associate with better metabolic outcomes. FRAAs are found in 60-70% of children with autism spectrum disorder, 47% of Belgian ASD children versus 3.3% of controls, and 63.8% of children with PANS/PANDAS. Rather than representing random pathology, this high prevalence suggests a potentially adaptive response.
A groundbreaking study published in Frontiers in Neuroscience (2016) examined 94 children with ASD and found that those with blocking FRAAs (which directly prevent folate from binding to receptors) showed significantly better outcomes compared to those with binding FRAAs or no antibodies:
- Higher total GSH/GSSG ratio (p=0.003)
- Higher free GSH/GSSG ratio (p=0.02)
- Lower inflammation markers (3-chlorotyrosine, p=0.03)
- Better communication scores
- Better stereotyped behavior scores
- Better social responsiveness
Children with blocking FRAAs represented what researchers called a “complementary metabolic endophenotype”—they had less severe ASD symptoms despite folate deficiency. The researchers concluded these children show better redox status, suggesting that reduced folate transport and slower methylation may be protective against oxidative stress accumulation.
In contrast, binding FRAAs (which trigger inflammation rather than directly blocking folate) showed higher serum B12 (suggesting impaired cellular uptake of multiple nutrients), more unfavorable redox profiles, and worse social skills. This differentiation supports the hypothesis that blocking methylation flux specifically, rather than inflammatory interference with receptors, provides the protective benefit.
The energy-oxidative stress tradeoff: methylation as moving forward at a cost
Methylation can be conceptualized as “moving forward with energy at a cost”—the cost being cumulative oxidative stress. This framework clarifies the biochemical tension between anabolic demands and oxidative damage accumulation.
High methylation activity provides clear benefits: better DNA synthesis and repair, normal homocysteine levels, proper neurotransmitter methylation, and adequate gene expression regulation. However, these benefits come with oxidative costs: higher mitochondrial ROS production through the ubiquinone pathway, more oxidative damage to proteins, DNA, and lipids, and accelerated aging markers.
Low methylation activity (from MTHFR variants, methionine restriction, or FRAAs) creates opposite tradeoffs: elevated homocysteine, potential DNA hypomethylation, and reduced SAM availability, but also lower mitochondrial ROS generation, less oxidative damage, extended lifespan in model organisms, and reduced cancer risk for certain tissue types.
The context determines which side of this equation dominates. Protection works best during post-developmental periods, in cancer-prone tissues like prostate and colon, in aging/longevity contexts, in high oxidative stress environments, and when baseline folate status is adequate. Dysfunction dominates during folate deficiency states, developmental periods requiring rapid cell division (like neural tube formation), and in tissues highly dependent on methylation like breast and endometrial tissue.
This represents a hormetic system where both extremes cause pathology. Dr. Chris Kresser noted: “Like many nutrients, methylation appears to follow a U-shaped curve, where both deficiency and excess cause pathology.” The heterozygote advantage seen in elderly populations with the CT genotype supports this—an intermediate methylation rate may represent an evolutionary sweet spot balancing biosynthetic capacity against oxidative burden.
Individual buffer capacity explains the tolerance spectrum
The dramatic variation in how people respond to methylation support—from immediate reactions to delayed crashes to sustained tolerance—can be explained by individual differences in oxidative stress buffer capacity. This buffer consists primarily of glutathione reserves, antioxidant enzyme activities, electrolyte stores, and cofactor availability.
Glutathione serves as the master antioxidant and primary buffer. The GSH/GSSG ratio in healthy cells exceeds 100:1, but under oxidative stress can drop to 10:1 or even 1:1. Research shows approximately threefold variation in red blood cell glutathione concentration between genetic strains, indicating substantial heritable differences in baseline capacity. Additionally, elderly individuals have 55% less glutathione than young controls, and polymorphisms in glutathione-related genes (GSTM1-null, GSTT1-null, GSTP1) affect 20-50% of populations.
The connection between glutathione and methylation creates a bidirectional vulnerability. Glutathione depletion leads to methionine depletion, which impairs methylation. Conversely, when methylation is stimulated, more homocysteine converts to methionine (via the methylation cycle) and less flows through the transsulfuration pathway to create cysteine and glutathione. This creates a competitive relationship where pushing methylation can deplete the very antioxidant systems needed to handle the oxidative burden methylation creates.
Dr. Ben Lynch identified three distinct response patterns that map directly to buffer capacity: immediate wonderful response (large buffer, rare), delayed crash pattern (moderate buffer that depletes, common), and immediate intolerance (already depleted buffer). The delayed crash pattern typically manifests as an amazing first week or two with improved mood, energy, and function, followed by a switch around weeks 2-4 to severe anxiety, irritability, muscle aches, headaches, and fatigue.
The mechanism of delayed problems involves progressive depletion of multiple buffers. Dr. Lynch explains: “Methylfolate supports methylation. Methylation supports cell growth and division… What happens when 10 billion cells divide? They become 20 billion cells. What is inside these cells? Magnesium and potassium—and glutathione. If any of these are deficient, then the cell does not function properly, gets sick and dies.”
Each round of cell division requires glutathione for protection, magnesium for enzymatic function, and potassium for membrane integrity. Initial reserves may be adequate for the first waves of increased cellular activity, but sustained high methylation activity over weeks progressively exhausts these buffers. Once the threshold is crossed where demand chronically exceeds supply capacity, symptoms manifest rapidly.
Pregnancy as the perfect storm: when both demands surge simultaneously
Pregnancy creates a unique scenario where methylation demands and oxidative stress both dramatically increase, potentially overwhelming women who start near their capacity ceiling. This helps explain why women with MTHFR variants or pre-existing oxidative stress show disproportionately high rates of pregnancy complications.
Pregnancy inherently increases oxidative stress through multiple mechanisms. The placenta, initially hypoxic, experiences a threefold increase in oxygen concentration when it connects to maternal circulation at the end of the first trimester, generating massive amounts of superoxide and nitric oxide in the syncytiotrophoblast. The metabolic demands of the mitochondria-rich placenta, systemic inflammatory response (particularly third trimester), and intermittent placental perfusion from inadequate spiral artery remodeling all contribute to sustained elevated ROS production.
Simultaneously, methylation demands surge. Genome-wide DNA methylation studies show 14,018 CpG sites with statistically significant methylation changes across pregnancy trimesters, regulating glucose homeostasis, immune adaptations, and placental function. The developing fetus requires enormous methylation for tissue differentiation, neural tube closure, brain development, and epigenetic programming. Recommended folate intake increases from 400 to 600 mcg daily, and choline, B12, methionine, and betaine demands all rise substantially.
These two challenges interact destructively. Oxidative stress causes direct DNA demethylation—ROS oxidizes 5-methylcytosine, leading to methyl group loss. Oxidative damage to DNA (8-OHdG formation) impairs methyltransferase binding and activity. Meanwhile, impaired methylation reduces expression of antioxidant defense genes. In preeclampsia, researchers found hypermethylation of the Nrf2 gene in placentas (70 preeclamptic versus 70 healthy pregnancies), which reduced expression of crucial antioxidant genes including heme oxygenase, superoxide dismutase, catalase, and glutathione peroxidase.
Women with MTHFR variants enter pregnancy with only 50-70% normal enzyme function, leaving minimal reserve capacity. When pregnancy doubles or triples methylation demands while simultaneously increasing oxidative stress, the system collapses. Elevated homocysteine from MTHFR variants directly generates ROS, damages vascular endothelium, promotes inflammation, and impairs placental function—creating a vicious cycle where methylation impairment worsens oxidative stress, which further damages methylation capacity.
Glutathione depletion during pregnancy exemplifies this cascade. Second-trimester glutathione levels are significantly lower than in non-pregnant women. Women with preeclampsia show markedly lower reduced glutathione in blood and placenta, decreased catalase activity, and poor total glutathione levels—the combination predicts preeclampsia severity. Women who miscarry show elevated extracellular glutathione, suggesting cells are releasing GSH due to damage rather than maintaining intracellular reserves.
This framework explains the clinical observation that some women experience significant, lasting health declines during or after pregnancy, particularly those entering pregnancy with high baseline oxidative stress from obesity, chronic disease, toxin exposure, or previous pregnancies without adequate recovery. They were already operating near their oxidative stress ceiling; pregnancy’s demands pushed them past the threshold.
Postpartum depletion: years to refill depleted buffers
The phenomenon of postnatal depletion syndrome, lasting 7-10 years or longer if unaddressed, reflects the profound time required to replenish exhausted oxidative stress buffers and methylation cofactors. Dr. Oscar Serrallach, who coined the term, identifies most postpartum issues as fundamentally neuro-inflammatory, driven by ongoing oxidative stress in brain tissue combined with inadequate omega-3s and antioxidants for recovery.
The nutrient debt is cumulative. Pregnancy depletes iron, zinc, B12, folate, vitamin D, magnesium, essential fatty acids, and amino acids. Birth creates additional acute losses through blood loss and tissue damage. Breastfeeding continues depletion—calorie and nutrient needs exceed even pregnancy levels. Without deliberate “refueling,” multiple pregnancies compound the deficit exponentially.
Mitochondrial dysfunction perpetuates the problem. Chronic oxidative stress damages mitochondria, but methylation is required for mitochondrial repair and biogenesis. Without both adequate antioxidants and methylation capacity simultaneously available, mitochondria cannot recover, resulting in the profound, unrelenting fatigue characteristic of severe postnatal depletion. Sleep deprivation perpetuates oxidative stress, breastfeeding increases metabolic demands and ROS production, and chronic parenting stress maintains elevated cortisol that generates additional oxidative damage.
The methylation-oxidative stress connection explains why simple “methylfolate supplementation” often fails or worsens postpartum symptoms. Pushing methylation without first addressing the oxidative stress burden and replenishing glutathione, magnesium, electrolytes, and other cofactors can accelerate cellular activity in an already-depleted system, hastening buffer exhaustion and triggering the cascade of “overmethylation” symptoms: anxiety, panic, irritability, insomnia, muscle aches, palpitations, and chemical sensitivities.
Clinical patterns: the threshold effect in action
Functional medicine practitioners consistently observe patients who initially thrive on methylation support but experience sudden deterioration after weeks to months—a pattern that precisely matches the buffer depletion model. The typical timeline involves days to 2-3 weeks of positive response (improved energy, mood, mental clarity), a transition period around weeks 2-4 where subtle symptoms may emerge, and full manifestation by weeks 3-6 where the person crashes into severe fatigue, anxiety, or physical symptoms.
Dr. Ben Lynch notes one particularly striking pattern: “Amazingly incredible week where they are happy, interacting and alert. Then the second week comes and they switch to wanting to hide in a room by themselves or literally throw dishes across the room out of anger” or become bedridden with muscle aches and joint pain. Patient reports echo this: “Felt amazing for two weeks, now worse than ever,” “Had to stop after a month—couldn’t sleep, heart racing, severe anxiety,” “Worked great initially, then gradual decline over 6-8 weeks.”
The mechanism behind “overmethylation symptoms” connects directly to oxidative stress. Excessive nitric oxide production explains many neurological symptoms—methylfolate increases nitric oxide, which effectively reduces headaches and cardiovascular disease risk, but excessive nitric oxide produces serious radical damage via peroxynitrite formation. Ramped-up catecholamine production (dopamine, norepinephrine, epinephrine) creates oxidative stress through neurotransmitter metabolism. High free copper from overmethylation inhibits glutathione synthesis, creating additional oxidative burden.
The difference between immediate reactions and delayed reactions maps to starting buffer status. Immediate reactors likely have very depleted baseline glutathione and cofactors, specific genetic polymorphisms affecting neurotransmitter metabolism (COMT, MAOA), pre-existing high inflammation consuming methyl groups, or gut dysbiosis interfering with B vitamin metabolism. They have essentially no buffer capacity remaining.
Delayed reactors start with adequate glutathione reserves, electrolytes, and cofactors, allowing methylation to catch up after chronic deficiency. Energy production improves, neurotransmitters normalize, detoxification engages—all positive initially. But weeks 2-6 see progressive buffer depletion through accelerated cell division consuming glutathione, magnesium and potassium depletion, cofactor consumption faster than replacement, cumulative oxidative stress from mobilized toxins, and insufficient protein to support continued methionine/methylation demands. Once buffer capacity is exceeded, symptoms cascade rapidly.
Biomarkers to assess current oxidative stress status
Practical biomarkers exist to assess someone’s oxidative stress buffer status before pushing methylation, potentially preventing predictable crashes. The ideal assessment combines markers of oxidative damage, antioxidant reserves, and methylation capacity.
The GSH/GSSG ratio serves as the single most important buffer capacity indicator. Normal cellular ratios exceed 100:1, but oxidative stress drives this to 10:1 or lower. Plasma normally shows approximately 3:1. Measuring both reduced (GSH) and oxidized (GSSG) glutathione provides critical insight into current reserve capacity. A ratio below 10:1 suggests compromised buffer capacity and poor tolerance for methylation interventions.
Testing can be performed through specialty labs using HPLC with electrochemical detection (gold standard) or enzymatic methods (commercial kits from Promega, Dojindo, Sigma-Aldrich). Clinical access is available through Access Medical Labs, Cell Science Systems Cellular Nutrition Assay, or Precision Point Advanced Oxidative Stress panel. The critical limitation is sample processing—glutathione samples must be processed within one hour with immediate deproteinization to prevent artifact oxidation.
For oxidative damage markers, 8-OHdG (8-hydroxy-2′-deoxyguanosine) in urine provides the most practical option. This DNA oxidation marker reflects total body oxidative DNA damage, predicts cancer and diabetes risk, and offers non-invasive collection with good stability. An optimal cut-off of 34.7 ng/mL provides 72% sensitivity and 92% specificity for disease detection. Values above 40 ng/mL suggest depleted buffer capacity. Available through Doctor’s Data or Vibrant Wellness for $150-200.
F2-isoprostanes represent the gold standard for oxidative stress measurement, specifically 8-iso-PGF2α measured by LC-MS/MS or ELISA. These lipid peroxidation products are chemically stable, specific, and present in all biological fluids. Urine collection is preferred for non-invasive monitoring. Available through Precision Point, Oxford Biomedical, or Vibrant Wellness, though more expensive ($150-200).
Homocysteine remains the most accessible methylation-related marker, available as a standard clinical lab test for $50-100. Normal levels below 10-12 μmol/L suggest adequate methylation capacity; elevation above 15 μmol/L indicates impaired methylation and increased oxidative stress. Importantly, homocysteine correlates with intracellular SAH (the methylation inhibitor), providing insight into methylation blockade.
The SAM/SAH ratio directly measures methylation capacity. Higher ratios indicate better methylation capacity; low SAM/SAH suggests decreased methylation potential. Elevated SAH is particularly significant as it potently inhibits methyltransferases. Available through Doctor’s Data Methylation Profile ($200-300), which includes SAM, SAH, ratio, homocysteine, cysteine, and methionine—providing comprehensive one-carbon metabolism assessment.
A practical tiered approach starts with screening everyone using homocysteine and basic inflammatory markers (CRP), then confirms abnormalities with GSH/GSSG ratio and an oxidative damage marker (8-OHdG or F2-isoprostanes), and investigates complex cases with comprehensive oxidative stress panels, SAM/SAH ratio, and mitochondrial function indicators. A minimum panel (homocysteine, glutathione, 8-OHdG, CRP) costs approximately $400; a comprehensive panel including SAM/SAH, F2-isoprostanes, and vitamin levels runs $1,000-1,200.
The decision framework based on these biomarkers suggests three categories: Green light (normal homocysteine under 10 μmol/L, normal oxidative markers, adequate GSH—proceed with methylation support); Yellow light (mild-moderate elevations, homocysteine 10-15—proceed with concurrent antioxidant support and close monitoring); Red light (homocysteine above 15, multiple elevated oxidative markers, GSH/GSSG below 10:1, high inflammation—address oxidative stress first before attempting methylation support).
Reframing the clinical approach: protection before acceleration
The evidence strongly supports a paradigm shift from viewing MTHFR variants and FRAAs as purely pathological to recognizing them as context-dependent adaptations that may protect against oxidative stress accumulation. Clinical approaches should assess whether someone’s current physiology represents protective slowdown near their oxidative threshold or true deficiency requiring supplementation.
Rather than universally supplementing methylation regardless of context, the protective slowdown hypothesis suggests asking: What is this person’s current oxidative stress burden? What is their buffer capacity? Are they already near their threshold? For someone with MTHFR variants who is functionally well, pushing methylation “to fix the genetics” may actually override a protective mechanism and create problems.
The sequence matters profoundly. Functional medicine consensus increasingly emphasizes addressing gut dysbiosis, reducing inflammation, and supporting antioxidant systems before methylation support. Dr. Ben Lynch states directly: “If you take methylfolate before inflammation is controlled, the methylfolate will worsen it.” Supporting glutathione 1-2 weeks before introducing methylfolate, ensuring adequate electrolytes (especially magnesium and potassium), and starting methylfolate at very low doses (50-200 mcg rather than 7.5-15mg) reduces the risk of overwhelming buffer capacity.
Rescue protocols for “overmethylation” focus on quenching excess SAM with niacin (nicotinic acid) 50-100mg, increasing electrolytes, supporting glutathione cautiously, using hydroxocobalamin to reduce excess nitric oxide, and switching to non-methylated forms (folinic acid, hydroxocobalamin instead of methylfolate and methylcobalamin). Some people require “pulse dosing”—taking methylation support for a few days then stopping for a week, allowing buffer replenishment between stimulation periods.
The research supports Dr. Lynch’s assertion that “It’s a common myth that you must take methylfolate daily. Like many myths, it’s wrong. You take methylfolate only when you need it.” Methylation support represents an intervention, not necessarily daily maintenance, and the need fluctuates based on demands, buffer status, and life circumstances.
Conclusion: embracing biochemical tradeoffs and individual thresholds
The protective slowdown hypothesis finds substantial support across multiple lines of evidence. Methionine restriction consistently extends lifespan and reduces oxidative stress across species by decreasing mitochondrial ROS production. MTHFR variants show protective associations with specific cancers and appear enriched in centenarian populations. The SAM-ubiquinone-ROS pathway provides direct mechanistic linkage between methylation flux and oxidative damage. Most remarkably, blocking folate receptor autoantibodies—which reduce methylation capacity—associate with better glutathione ratios and lower inflammation in affected children.
The central insight is that methylation represents a fundamental biochemical tradeoff between anabolic capacity and oxidative burden. Neither extreme proves universally beneficial; context, life stage, genetic background, toxic burden, and current buffer capacity all determine whether faster or slower methylation serves an individual better at a given time.
Individual variation in buffer capacity—primarily glutathione reserves, antioxidant enzyme activities, electrolyte stores, and cofactor availability—explains the spectrum of responses to methylation support. Large buffers allow sustained tolerance, moderate buffers lead to initial success followed by delayed crashes as reserves deplete, and depleted buffers cause immediate reactions. The consistent clinical pattern of people tolerating methylation support for weeks to months before experiencing threshold effects directly reflects progressive buffer exhaustion.
Pregnancy exemplifies the vulnerability of operating near oxidative capacity. Simultaneous surges in oxidative stress (placental metabolism, inflammatory responses) and methylation demands (fetal development, maternal adaptations) can overwhelm women with MTHFR variants or pre-existing stress burdens, explaining pregnancy complications and the profound, years-long postnatal depletion many women experience.
Practical biomarkers allow assessment of oxidative stress status before intervention: GSH/GSSG ratio for buffer capacity, 8-OHdG or F2-isoprostanes for oxidative damage, homocysteine for methylation-related stress, and SAM/SAH ratio for methylation capacity. These tools enable personalized decisions about whether to support methylation or first address oxidative burden.
The paradigm shift this research suggests moves from viewing slower methylation as universally dysfunctional requiring correction toward recognizing it may represent protective adaptation in individuals near their oxidative threshold. Clinical practice should assess individual context—oxidative burden, buffer capacity, inflammation, life stage—before deciding whether to accelerate or protect methylation systems. For many people, especially those with MTHFR variants who are functionally well, the “dysfunction” may be providing protection worth preserving rather than overriding.
This framework offers hope for better individualizing interventions, preventing predictable crashes from buffer depletion, understanding pregnancy complications, and recognizing that optimizing health sometimes means respecting protective slowdowns rather than pushing systems toward theoretical ideals that may prove harmful in practice.
