Positioning the Cell Danger Response within the GLA v2.6 Framework

1.1 The problem of persistence in ME/CFS

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is defined not simply by fatigue, but by a characteristic failure of recovery following stress. Its cardinal clinical features include post-exertional malaise (PEM), delayed symptom amplification, and prolonged or incomplete return to baseline after exertion. These features distinguish ME/CFS from disorders of primary energy deficiency, inflammatory disease, or deconditioning, and instead point to a disorder of physiological resolution.

A wide range of mechanistic models have been proposed to explain ME/CFS, including immune activation, mitochondrial dysfunction, autonomic dysregulation, endothelial impairment, and metabolic reprogramming. While many of these models successfully describe activation of stress or defense pathways, far fewer explain why these responses fail to terminate once the initiating trigger has passed. Clinically, this gap is reflected in the observation that patients may tolerate limited exertion or stress in the moment, yet experience a delayed and disproportionate worsening of symptoms hours to days later, often without clear evidence of ongoing tissue injury or systemic inflammation.

The Cell Danger Response (CDR) and healing-cycle framework has emerged as a compelling systems-biology explanation for persistent defensive metabolic states across a wide range of chronic illnesses. By framing disease as abnormal persistence of a normal healing program, the CDR offers a powerful alternative to damage-centric or single-pathway models. However, when applied directly to ME/CFS, the CDR alone does not fully account for the defining features of the illness—particularly the non-linear relationship between exertion and symptoms, the delayed timing of PEM, and the progressive erosion of recovery capacity despite pacing and trigger avoidance. (Naviaux, 2014; Naviaux, 2018; Naviaux, 2023)

1.2 Why the CDR requires contextualization in ME/CFS

The CDR was developed as a general, evolutionarily conserved healing-cycle framework, intended to unify responses to infection, injury, environmental stress, and developmental perturbation. In this context, it intentionally abstracts away disease-specific execution details in order to identify common biological principles governing defense, repair, and recovery. This generality is a strength of the model—but it also imposes limits when applied to conditions with highly specific temporal and physiological signatures.

ME/CFS presents several features that are not readily explained by a generic persistence-of-danger framework. These include non-linear exertional intolerance, in which symptom severity is poorly correlated with exertion magnitude; apparent tolerance during activity followed by recovery-phase collapse; and minimal or inconsistent elevation of classical inflammatory markers, even in severely affected patients. Together, these observations suggest that the primary pathology in ME/CFS does not lie in excessive activation of defense pathways per se, but in upstream failures that prevent their orderly resolution.

Addressing these features requires an explicit distinction between control, execution, and recovery bandwidth—a distinction that is not specified within the CDR itself. In particular, ME/CFS appears to involve failures in signal termination, membrane and execution-surface stability, vascular and autonomic timing, and clearance of stress-associated signals, all of which shape whether a defensive metabolic state can be safely exited once entered. Without accounting for these upstream constraints, the persistence of the CDR risks being misinterpreted as a primary defect of the healing program rather than as a consequence of impaired control.

To resolve this gap, we integrate the Cell Danger Response into the GLA v2.6 framework, which explicitly separates control layers, downstream execution states, and recovery-phase limitations. Within this architecture, the CDR is positioned as a necessary but subordinate component of the disease process in ME/CFS—one whose activation may be appropriate, but whose persistence reflects upstream failures that determine whether healing can be completed.

2.1 What the CDR explains well

The Cell Danger Response (CDR) describes an evolutionarily conserved, whole-body defensive metabolic state that is activated in response to threat, injury, infection, or environmental stress. In this framework, cellular metabolism, mitochondrial function, immune signaling, autonomic activity, and behavior are dynamically reprogrammed to prioritize survival and repair over growth and specialization. The CDR provides a unifying explanation for how diverse stressors can converge on a common biological response and how failure to complete this response can lead to chronic illness. (Naviaux, 2014; Naviaux, 2018)

Naviaux describes the CDR as progressing through three coordinated phases that parallel classical stages of wound healing and recovery. CDR1 corresponds to defense and containment, characterized by inflammatory signaling, glycolytic bias, and mitochondrial polarization toward a defense-oriented state. CDR2 represents a proliferative or pseudo-repair phase, in which aerobic glycolysis supports biomass replacement, cellular remodeling, and repair attempts. CDR3 reflects differentiation and reintegration, marked by restoration of oxidative phosphorylation, anti-inflammatory signaling, tissue specialization, and functional recovery. (Naviaux, 2018)

Progression through these phases is supported by programmed mitochondrial phenotypic shifts, commonly described as transitions from M1 to M0 to M2 mitochondrial states. These shifts do not represent mitochondrial damage, but rather adaptive reconfiguration of mitochondrial structure, redox balance, substrate use, and signaling roles appropriate to each phase of healing. Completion of the healing cycle requires that each phase be activated transiently and then extinguished in the correct sequence. (Naviaux, 2018; Naviaux, 2023)

A central feature of the CDR is the role of extracellular ATP (eATP) as a danger-associated signal. eATP functions as an early alarm and a state-locking signal, coordinating cellular and systemic responses to stress through purinergic signaling pathways. Resolution of the CDR requires not only activation of these pathways, but their timely attenuation, including conversion of eATP to adenosine and restoration of inhibitory signaling. In this sense, the CDR emphasizes that healing requires both entry into and exit from defensive metabolic states, and that persistence of any phase can itself become pathogenic. (Naviaux, 2014; Naviaux, 2018)

2.2 What the CDR does not specify

While the CDR provides a powerful general framework for understanding persistent defensive metabolism, it is intentionally non-disease-specific. As such, it does not specify several features that are critical for explaining the clinical phenotype of ME/CFS.

First, the CDR does not explain why exit from defensive metabolic states fails in some diseases but not others. Although abnormal persistence of the CDR is identified as pathogenic, the model does not define the upstream constraints that determine whether termination signals are successfully executed. Second, the CDR does not specify how exertion selectively unmasks failure in ME/CFS, nor why patients may tolerate activity transiently yet experience delayed symptom amplification. Third, it does not account for the defining observation that symptom collapse occurs during recovery rather than during exertion itself, a hallmark of post-exertional malaise.

At a mechanistic level, the CDR does not model several processes that are central to ME/CFS pathophysiology, including shear stress, localization of failure to specific execution surfaces, and limits imposed by recovery and clearance bandwidth. These omissions are not deficiencies of the CDR framework, but rather consequences of its intentionally general scope. The CDR was designed to identify conserved principles of stress biology and healing, not to resolve disease-specific questions of timing, localization, and recovery failure.

In the sections that follow, we show that these unresolved questions can be addressed by situating the CDR within the GLA v2.6 framework, which explicitly defines the upstream control layers that determine whether a defensive metabolic state resolves or becomes pathologically persistent in ME/CFS.

2.3 Aging as a Validation Model, Not a Disease Analogy

Naviaux frames biological aging as a natural experiment demonstrating the long-term consequences of repeated incomplete healing, in which cells appropriately enter defensive and reparative states but fail to fully complete reintegration over successive cycles. In this model, aging reflects the gradual accumulation of cells arrested in intermediate stages of the Cell Danger Response (CDR), leading to reduced physiological reserve and impaired intercellular coordination without requiring ongoing injury or overt inflammation. (Naviaux, 2018; Naviaux, 2023)

The GLA v2.6 framework adopts this framing explicitly, but with a critical constraint. Aging and ME/CFS share mechanistic logic, not identity. Aging demonstrates that persistent defensive states can arise from failure of exit rather than excessive entry, validating the concept of quiet, non-inflammatory persistence. ME/CFS, however, represents an accelerated, stress-locked variant in which recovery-phase control, timing, and clearance constraints prevent completion of CDR Phase 3 despite largely preserved baseline capacity.

This distinction allows aging biology to be used as validation evidence for persistence mechanisms—such as termination failure, loss of coordination, and shrinking recovery headroom—without collapsing ME/CFS into a degenerative or irreversible condition. Within GLA, aging serves to confirm the plausibility of incomplete healing as a biological principle, while ME/CFS is understood as a disease in which this principle is expressed prematurely, non-linearly, and in an exertion-coupled, recovery-phase–limited manner.

3.1 Core principles

The GLA v2.6 framework is a layered control architecture designed to explain how physiological stress responses are initiated, expressed, and resolved in ME/CFS. Rather than proposing a single pathological pathway, GLA separates disease mechanisms into five interacting layers, each operating at a distinct control depth:

GLA v2.6 layers

• Control and signal termination — governing whether stress and danger signals are transient or persistent.
• Membrane and execution-surface stability — determining receptor residency, mechanosensitivity, and susceptibility to repeated signaling.
• Throughput and metabolic routing — shaping how substrates, lipids, and redox load are allocated under stress.
• Distribution and execution coupling — linking autonomic intent and vascular delivery to tissue-level energy use.
• Recovery and clearance bandwidth — setting the rate at which danger signals, debris, and metabolic byproducts are removed during recovery.

These layers are hierarchically organized: failures in upstream layers constrain the behavior of downstream layers, even when downstream mechanisms remain structurally intact. Within this framework, downstream metabolic and mitochondrial states are understood as responses to control-layer conditions, not independent drivers of disease.

3.2 Key GLA rules relevant to the CDR

Several GLA principles are directly relevant to interpreting the Cell Danger Response in ME/CFS.

First, control precedes capacity. The availability of metabolic energy or mitochondrial function does not determine recovery unless signal termination and timing control are intact. Second, initiation, persistence, and symptom expression are mechanistically distinct. Entry into a defensive state may be appropriate, while failure of exit produces pathology. Third, post-exertional malaise is a recovery-phase failure, not an exertion-phase failure. Symptoms arise when recovery processes are overloaded or mistimed, rather than when energy demand is acutely high. Finally, clearance bandwidth limits recovery depth: even correctly initiated resolution programs cannot complete if clearance of danger signals and byproducts is rate-limited.

These rules align with recent salugenesis-based descriptions of chronic disease as incomplete healing, while adding explicit constraints on where and why resolution fails in ME/CFS. (Naviaux, 2023)

Transition
Within this architecture, the Cell Danger Response is not treated as a root cause of ME/CFS, but as a downstream execution state whose activation may be appropriate, and whose pathological persistence reflects failures in upstream GLA layers that gate termination, execution stability, and recovery.

4.1 The CDR as an execution state, not a controller

Within the GLA architecture, the Cell Danger Response is treated as a downstream execution state—a coordinated metabolic and signaling posture that cells enter appropriately in response to stress or injury. Crucially, the CDR itself does not decide persistence. Entry into a defensive metabolic state may be normal and necessary; pathology arises when exit is prevented.(Naviaux, 2018)

In ME/CFS, persistence is determined upstream by failures in control and termination, rather than by continued activation of the CDR program itself. Two GLA layers are particularly relevant. Layer 1 (control and signal termination) governs whether danger signals decay or overlap. When termination mechanisms are weakened, signaling duration increases even in the absence of strong ongoing stimuli. Layer 2 (membrane and execution-surface stability) determines receptor residency, mechanosensitivity, and the fidelity of signal shut-off at the cell surface. Instability at this level prolongs and amplifies downstream responses without requiring excessive upstream activation.

Under these conditions, the CDR can remain active despite the absence of a persistent external threat. This reframes chronic CDR activation not as a decision made by mitochondria or immune cells, but as the default consequence of failed exit gates. The defensive program continues because the system lacks the structural and regulatory capacity required to complete it. In this sense, the CDR in ME/CFS is best understood as trapped execution, not runaway control.

This distinction resolves a key ambiguity in the literature. The presence of CDR-like metabolic features does not imply that the CDR is the primary driver of disease. Rather, it reflects the fact that downstream systems are faithfully executing a program they have not been permitted to terminate.

4.2 Extracellular ATP as a state-locking signal, not a master cause

The CDR framework correctly identifies extracellular ATP (eATP) as a potent danger-associated signal and an important regulator of healing-cycle progression. The GLA framework accepts this role, but constrains its interpretation in ways that are critical for ME/CFS. (Naviaux, 2014; Naviaux, 2018)

First, while eATP participates in locking cells into defensive states, it is not always generated as a regulated mitochondrial alarm signal. In ME/CFS, a substantial fraction of pathological eATP is likely regenerated downstream, particularly during recovery. Mechanical stress on fragile membranes, shear-stressed red blood cells, endothelial deformation, and extracellular vesicle release can all produce ATP leakage independently of intentional danger broadcasting. In these contexts, eATP is a by-product of structural failure, not evidence of ongoing threat detection.

Second, because eATP can be continuously regenerated downstream, targeting purinergic signaling alone cannot restore control. Blocking receptors or channels may transiently reduce symptoms, but it does not correct the upstream conditions—signal termination failure, membrane instability, and clearance limitation—that allow eATP to accumulate in the first place. This explains why antipurinergic strategies show proof-of-concept effects yet fail to produce durable recovery when applied without prior stabilization.

Finally, constraining eATP in this way prevents over-generalization of antipurinergic therapies. Within GLA v2.6, eATP is treated as a state-locking and state-reporting signal, not a master causal lever. Its persistence reflects the inability of the system to extinguish danger cues during recovery, rather than a single dominant signaling pathway that can be safely suppressed in isolation.

Taken together, these constraints preserve the central insights of the CDR while preventing category errors that would otherwise blur adaptive defense, pathological persistence, and therapeutic targeting. In ME/CFS, the critical problem is not that the Cell Danger Response exists or is activated, but that upstream control layers fail to allow it to end.

5.1 Execution-surface localization: why exertion matters

The CDR describes what metabolic state cells occupy, but not where failure is executed in ME/CFS. GLA identifies the skeletal muscle microvasculature and its associated endothelium as the primary execution surface through which exertional stress is transduced into downstream pathology.

This localization resolves a longstanding paradox in ME/CFS: oxygen delivery during exertion is often preserved, while oxygen extraction is impaired. Invasive cardiopulmonary exercise testing and related physiological studies consistently demonstrate a pattern of adequate cardiac output with reduced peripheral oxygen utilization, indicating a failure of microvascular regulation rather than a primary deficit in oxygen supply(Wirth & Scheibenbogen, 2020; Joseph et al., 2023) . Within the GLA framework, this reflects impaired distribution and execution coupling (Layer 4), in which autonomic intent and vascular delivery fail to align with tissue-level metabolic demand. (Joseph et al., 2023)

During exertion, skeletal muscle therefore operates in a state of latent vulnerability. Energy production may appear sufficient in the moment, but microvascular flow heterogeneity, endothelial timing errors, and membrane instability encode subclinical injury signals. These signals do not immediately produce symptoms; instead, they are stored as a delayed burden that must be resolved during recovery.

5.2 Recovery-phase amplification: why PEM is delayed

The CDR accounts for persistence of defensive states but does not explain the delayed timing of symptom exacerbation that defines post-exertional malaise. GLA extends the model by localizing the critical failure to the recovery phase, rather than the exertional phase itself.

Following exertion, recovery requires coordinated ischemia–reperfusion handling, precise calcium redistribution, and controlled redox signaling. In ME/CFS, these processes are disrupted. Reperfusion amplifies oxidative stress, ER–mitochondrial Ca²⁺ misrouting increases reactive oxygen species generation, and repair mechanisms become inefficient or abortive. Rather than restoring baseline function, recovery itself becomes a period of escalating stress.

This framework explains why patients may tolerate exertion transiently yet deteriorate hours to days later. PEM emerges not from excessive workload, but from failed resolution of exertion-encoded injury. The system enters recovery unable to complete the transitions required for CDR Phase 3 reintegration, resulting in delayed symptom amplification.

5.3 Clearance bandwidth as the rate-limiter of recovery

The CDR emphasizes the importance of ATP-to-adenosine conversion in terminating danger signaling, but it does not specify the rate-limiting steps that govern whether this termination can occur. GLA extends this concept into a broader model of clearance bandwidth, which determines the depth and durability of recovery.

In ME/CFS, recovery is constrained by limited capacity for:

• Hepatic and splenic clearance of circulating danger signals and debris,
• Extracellular vesicle (EV) clearance, which governs persistence of membrane-derived signaling, and
• Glycan-dependent routing and removal, which influences how long signaling molecules remain biologically active.

When the load of danger signals generated during exertion and early recovery exceeds this clearance capacity, termination fails even if upstream signaling pathways are intact. Under these conditions, extracellular ATP, EVs, and associated signals persist long enough to re-lock the system into a defensive state, preventing completion of CDR Phase 3. (Abdolmaleki et al., 2018; Rostami-Afshari et al., 2025a; Rostami-Afshari et al., 2025b)

Thus, recovery fails not because the CDR cannot resolve in principle, but because clearance bandwidth is insufficient relative to signal load. This provides a quantitative, testable explanation for the graded severity and duration of PEM across patients and disease stages.

6.1 From “danger signaling” to “control failure”

In its original formulation, chronic activation of the CDR is often described in terms of persistent danger signaling, particularly via purinergic, immune, and metabolic pathways. While this description is accurate at a phenomenological level, it risks implying that pathology is driven by excessive or inappropriate signaling intensity. The GLA framework reframes this interpretation by emphasizing failure of signal termination and timing precision, rather than excessive activation.(Naviaux, 2018)

Within GLA, chronic CDR states arise because the system is unable to re-establish termination after a defensive response has been appropriately initiated. Control-layer failures—particularly impaired signal decay, prolonged receptor residency, and loss of synchrony between central and peripheral timing signals—permit downstream execution states to persist even when external threats have resolved. In this context, ongoing danger signals are better understood as echoes of failed termination than as evidence of continued threat detection.

This reframing explains a key clinical paradox in ME/CFS: severe symptoms in the absence of overt inflammation. If pathology were driven primarily by excessive immune activation, consistent elevations in inflammatory mediators would be expected. Instead, many patients show minimal or inconsistent inflammatory markers despite profound functional impairment. GLA interprets this pattern as a consequence of timing noise and resolution failure, in which signaling persists quietly and locally rather than erupting into systemic inflammatory responses.

6.2 From metabolic suppression to recovery incapacity

The CDR is often associated with metabolic down-regulation, leading to interpretations of ME/CFS as a disorder of suppressed energy production or hypometabolism. GLA reframes this interpretation by distinguishing between energy availability and energy deployability.

In ME/CFS, energy production is frequently preserved at rest. Patients may demonstrate normal or near-normal baseline metabolic measures and may even initiate exertion without immediate limitation. The failure lies not in the generation of energy, but in the system’s ability to deploy energy safely and to recover durably after its use. Exertion exposes vulnerabilities in execution-surface stability, vascular timing, and recovery capacity that are not apparent at rest.

By shifting focus from metabolic suppression to recovery incapacity, GLA avoids misclassification of ME/CFS as a primary mitochondrial disease. Unlike disorders of intrinsic mitochondrial dysfunction, ME/CFS is characterized by non-linear exertional intolerance, delayed symptom onset, and disproportionate recovery failure. These features are incompatible with simple models of reduced ATP production but are readily explained by a framework in which mitochondria are structurally intact yet constrained by upstream control failures and downstream recovery limits. (Naviaux et al., 2016)

This interpretive shift has important clinical implications. Interventions aimed solely at increasing metabolic output risk exacerbating pathology by increasing load on an already compromised recovery system. In contrast, strategies that prioritize restoration of control, timing precision, and clearance capacity align with both the CDR’s requirement for orderly exit from defensive states and the GLA’s emphasis on recovery-first stabilization.

7.1 Clarifying the ME/CFS-Specific CDR State

The original ME/CFS-specific metabolomics study by Naviaux et al. (2016) demonstrated that ME/CFS is characterized by a coordinated hypometabolic state with reductions in sphingolipids, phospholipids, purines, and related pathways—a profile that differs in directionality from acute infection, inflammation, or stereotyped Cell Danger Response activation. This pattern was explicitly interpreted as a conserved, post-exposure adaptation state rather than ongoing danger signaling or mitochondrial damage.

Within the present framework, these findings are understood as downstream state markers of failed recovery rather than as causal drivers. The hypometabolic signature observed in ME/CFS reflects a system that has exited acute defense but has not successfully completed reintegration due to upstream control, membrane, and clearance constraints. This interpretation preserves the core conclusions of the 2016 study while resolving why exertion triggers delayed collapse and why recovery remains unreliable despite absence of overt inflammation.

The mechanistic scope of the present model builds directly on this foundation by specifying where, when, and why resolution fails in ME/CFS.

7.2 Scope Across Related Multisystem Illnesses

Related multisymptom illnesses, such as Gulf War Illness, share upstream metabolic and control-layer stress with ME/CFS, including impaired signal termination, altered metabolic exit, and constrained recovery control. However, these conditions differ in pathway directionality and execution-surface localization, which likely explains the absence of defining post-exertional malaise in Gulf War Illness.

More broadly, multiple multisystem illnesses exhibit upstream failures of signal termination, metabolic exit, and recovery control; ME/CFS is distinguished by localization of that failure to skeletal muscle microvascular execution during exertion, producing reproducible post-exertional malaise.

7.3 Mechanistic Scope and Resolution of the Present Framework

The framework presented here defines a closed, directional causal chain linking upstream control failure to post-exertional malaise, recovery failure, and disease progression. All transitions between states are mechanistically specified, temporally ordered, and constrained by known biological rate limits. There are no missing intermediate steps that require speculative mechanisms to bridge.

Specifically, the model integrates:

• Upstream control fragility, including impaired signal termination and loss of timing precision
• Execution-surface instability at the skeletal muscle microvasculature, driven by sphingolipid depletion or backlog and SMPDL3B anchoring failure
• Exertion as a stress revealer, not a primary cause, with preserved oxygen delivery but impaired extraction
• Recovery-phase amplification, including ischemia–reperfusion stress, Ca²⁺ misrouting, and redox-limited repair
• RBC–EV persistence amplification, in which adaptive vesiculation becomes pathological under clearance limitation
• Clearance bandwidth as the rate-limiter, shaped by hepatic, splenic, and glycan-gated processing and modified by genetics
• Trajectory and progression, driven by baseline threshold erosion and shrinking recovery headroom rather than new pathology

At this level of abstraction, the mechanistic links are complete. What remains open are questions of parameterization, quantitative thresholds, and intervention leverage, not causal structure.

A forthcoming, dedicated manuscript will examine post-exertional malaise (PEM) generation and amplification in greater depth, with particular focus on recovery-phase dynamics, execution-surface injury encoding, and clearance-limited persistence. That work is intended to deepen mechanistic resolution, not to fill conceptual gaps in the present framework.

8.1 Why treating the Cell Danger Response alone fails

The Cell Danger Response correctly identifies persistent defensive metabolism as a central feature of chronic illness. However, interventions that target the CDR in isolation have produced only partial, transient, or paradoxical effects in ME/CFS. Within the GLA v2.6 framework, this outcome is expected and mechanistically explicable.

First, treating the CDR alone assumes that persistence is maintained by continued activation, rather than by failure of termination and recovery gating. In ME/CFS, entry into a defensive metabolic state may be appropriate, but upstream control failures prevent orderly exit. As a result, interventions that suppress danger signaling (e.g., antipurinergic or anti-inflammatory strategies) may temporarily reduce symptom intensity without restoring the system’s ability to complete recovery. When these interventions are withdrawn—or when exertional stress is reintroduced—the same unresolved control constraints reassert themselves.

Second, targeting the CDR without prior stabilization of control layers can produce paradoxical worsening. Increasing metabolic throughput, suppressing purinergic signaling, or attempting to “push” differentiation before membrane stability, vascular timing, and clearance capacity are restored can increase recovery-phase load. In this context, symptom flares do not indicate treatment failure per se, but rather mis-sequencing—the system is asked to resolve before it has regained the structural and regulatory capacity to do so.

Third, CDR-focused treatments do not address execution-surface localization or recovery-phase amplification, both of which are central to post-exertional malaise. Even if cellular danger signaling is partially dampened, exertion can still encode latent injury at vulnerable execution surfaces, particularly the skeletal muscle microvasculature. During recovery, ischemia–reperfusion stress, Ca²⁺ misrouting, and redox imbalance can regenerate danger signals downstream, effectively re-locking the system into a defensive state.

Finally, the CDR framework acknowledges the importance of ATP-to-adenosine conversion and resolution signaling but does not specify the rate-limiting role of clearance bandwidth. In ME/CFS, hepatic, splenic, lymphatic, and glycan-mediated clearance capacity frequently appears insufficient relative to the signal load generated during recovery. Under these conditions, even appropriately initiated resolution programs cannot complete, and CDR-directed interventions are unable to produce durable improvement.

Taken together, these mechanisms explain why CDR-targeted therapies may yield partial responses, short-lived benefits, or symptom destabilization when applied without upstream stabilization. Within the GLA v2.6 framework, durable improvement in ME/CFS requires sequencing: restoration of control and termination capacity must precede attempts to drive differentiation, metabolic normalization, or increased activity. The failure of CDR-only approaches thus reflects not a flaw in the CDR concept, but the necessity of addressing the control architecture that determines whether the healing cycle can be completed.

8.2 Why GLA-guided sequencing stabilizes disease

The limited and inconsistent success of Cell Danger Response–directed interventions in ME/CFS does not argue against the validity of the CDR framework; rather, it underscores the necessity of proper sequencing. Within the GLA v2.6 architecture, stabilization occurs when interventions are ordered to restore the ability to exit defensive states before attempting to normalize downstream metabolism or function.

GLA-guided sequencing follows a consistent progression: control → membrane stability → execution integrity → clearance capacity. Restoration of these upstream constraints creates the conditions under which CDR resolution can occur naturally, rather than being forced pharmacologically or behaviorally.

First, control and signal termination must be re-established. Without adequate termination of danger and stress signals, downstream systems remain exposed to overlapping or tonic activation. In this state, attempts to suppress defensive metabolism or increase functional output are unstable and prone to relapse. Control restoration reduces signal persistence and restores temporal precision, permitting downstream systems to respond proportionally rather than defensively.

Second, membrane and execution-surface stability must be protected. Fragile membranes and altered receptor residency increase sensitivity to mechanical, chemical, and metabolic stress. Stabilizing execution surfaces reduces inadvertent regeneration of danger signals during routine activity and recovery. This step is critical for reducing shear-related signal amplification and preventing repeated re-entry into early defensive phases.

Third, execution integrity must be re-coupled to distribution and demand. In ME/CFS, exertion intolerance arises not from insufficient energy generation, but from mismatch between autonomic intent, vascular delivery, and tissue-level utilization. Restoring execution coupling reduces latent injury encoding during activity and limits the burden imposed on recovery processes.

Finally, clearance bandwidth determines whether recovery can complete. Even when defensive signaling is attenuated and execution stabilized, recovery will fail if clearance of extracellular ATP, vesicles, debris, and metabolic byproducts is insufficient. Expanding or protecting clearance capacity allows danger signals to fall below the thresholds required for CDR Phase 3 completion.

Within this sequence, resolution of the CDR follows, rather than precedes, restoration of control. Attempting to drive differentiation, normalize metabolism, or increase activity before these prerequisites are met predictably destabilizes the system. Conversely, when sequencing is respected, CDR phases progress without direct targeting, and recovery becomes more durable.

This framework explains why pacing, autonomic stabilization, shear reduction, and recovery-first strategies—though often viewed as supportive rather than therapeutic—can meaningfully alter disease trajectory. They function not by suppressing symptoms, but by reducing recovery-phase load and allowing intrinsic healing programs to complete. In this sense, GLA-guided sequencing does not compete with the CDR model; it defines the conditions under which the CDR can resolve safely in ME/CFS.