What a Human Trial of Rapamycin in Chronic Fatigue Syndrome Reveals About Autophagy and Aging

A Cellular Explanation for Exertional Collapse

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains one of the most enigmatic chronic illnesses in modern medicine. Patients experience profound fatigue, cognitive dysfunction, pain, and autonomic instability—but the defining feature of the disease is post-exertional malaise (PEM): a delayed, often prolonged worsening of symptoms triggered by even minor physical or mental exertion. Unlike ordinary fatigue, PEM can last days or weeks and frequently leaves patients functionally incapacitated. Over time, repeated or overlapping PEM episodes may accumulate, potentially driving long-term physiological decline.

Despite affecting an estimated three million people in the United States, ME/CFS has no FDA-approved treatments. Current therapies focus on symptom management rather than disease modification, and responses vary widely across patients. One reason is that the underlying biology of ME/CFS remains poorly defined. The illness spans multiple systems—metabolic, neurological, immune, and autonomic—making it difficult to identify a unifying mechanism that explains both the disease itself and its hallmark sensitivity to exertion.

Over the past decade, however, a converging body of evidence has begun to point toward disrupted cellular energy management as a central theme. Studies have reported impairments in glycolysis, reduced mitochondrial oxygen consumption, altered energy metabolism, and abnormalities in cellular stress responses. Together, these findings suggest that ME/CFS may involve a failure of cells to adapt appropriately to metabolic demand—a vulnerability that becomes painfully apparent after exertion.

One process increasingly implicated in this failure is autophagy, the cell’s internal recycling and repair system. Autophagy allows cells to clear damaged proteins and dysfunctional mitochondria while reallocating resources during periods of stress. In healthy physiology, this system is tightly regulated and dynamically engaged during energy scarcity or increased demand. When autophagy is impaired, cells accumulate damage, inflammatory signaling increases, and energy production becomes inefficient—conditions that closely resemble the physiological state observed in ME/CFS.

Researchers at the University of Wisconsin–Milwaukee began probing this connection by examining autophagy-related signaling in ME/CFS patients. In earlier work, they observed elevated levels of ATG13, a protein essential for initiating autophagy. But closer inspection revealed a paradox: ATG13 was heavily phosphorylated at a site that renders it functionally inactive. In other words, the machinery required to initiate cellular cleanup was present—but locked in an “off” position.

...the machinery required to initiate cellular cleanup was present—but locked in an “off” position.

That observation raised a critical mechanistic question: what was preventing autophagy from functioning properly?

The answer appeared to lie upstream, in a master regulator of cellular growth and metabolism known as mTOR (mechanistic target of rapamycin). mTOR acts as a molecular switch, toggling cells between growth and maintenance modes depending on nutrient availability. When mTOR activity is high, autophagy is suppressed. When mTOR activity is reduced, autophagy is released to perform cellular maintenance and repair.

In follow-up experiments, the researchers showed that excessive mTOR signaling could phosphorylate ATG13 in a way that disrupts early autophagy initiation. In animal models, genetic disruption of ATG13, and therefore autophagy levels, produced severe exercise-induced fatigue—mirroring the defining clinical feature of ME/CFS. Pharmacological activation of mTOR, inhibiting autophagy initiation, produced similar effects, including muscle inflammation, immune cell infiltration, and nerve demyelination—pathologies consistent with chronic inflammatory stress.

Together, these findings suggested a unifying hypothesis: ME/CFS may represent a state of impaired autophagy driven by inappropriate mTOR activation, leaving cells unable to recover from even modest energetic stress. If true, restoring autophagy—rather than suppressing symptoms—could address a root biological vulnerability of the disease.

ME/CFS may represent a state of impaired autophagy driven by inappropriate mTOR activation, leaving cells unable to recover from even modest energetic stress. If true, restoring autophagy—rather than suppressing symptoms—could address a root biological vulnerability of the disease.

This hypothesis naturally led the investigators to consider rapamycin, a selective mTOR inhibitor with a long clinical history. Originally approved as an immunosuppressant for organ transplantation and later used in cardiovascular and oncology settings, rapamycin is now widely studied as a geroprotective agent due to its ability to stimulate autophagy and modulate the harmful effects of cellular senescence. Importantly, low-dose, intermittent rapamycin has been shown to stimulate autophagy without inducing the toxicities associated with chronic high-dose exposure that organ transplant patients are prescribed.

On this basis, the researchers initiated an observational study to examine whether low-dose, once-weekly rapamycin could alleviate core ME/CFS symptoms—particularly fatigue and post-exertional malaise—by restoring autophagy signaling. Rather than testing rapamycin as a nonspecific anti-inflammatory or immunosuppressant, the study was designed to probe a more targeted biological question: could correcting autophagy dysfunction translate into meaningful clinical improvement in ME/CFS patients?

The remainder of this review examines how the investigators approached that question, what they observed clinically and biologically, and what their findings suggest about autophagy as a therapeutic target in ME/CFS.

Study Design: Testing a Biological Hypothesis in Patients

To explore whether restoring autophagy could translate into meaningful clinical improvement in ME/CFS, the investigators designed a longitudinal, observational study centered on a simple but biologically motivated intervention: low-dose, intermittent inhibition of mTOR using rapamycin.

Rather than testing rapamycin as a broad immunosuppressant, the study was structured to evaluate it as a targeted probe of autophagy. Participants received a once-weekly dose of rapamycin (6 mg/week)—a schedule chosen to modulate mTOR signaling without continuous suppression. This intermittent approach reflects the idea that autophagy is most effectively engaged in pulses rather than chronically, while also minimizing the adverse metabolic and immunologic effects associated with daily dosing.

A total of 86 individuals with ME/CFS were enrolled, all meeting established diagnostic criteria. Forty participants completed the full 90-day protocol at the time of analysis, with additional participants still undergoing follow-up. The study unfolded over four predefined time points: a pretreatment baseline, followed by three on-treatment assessments spanning approximately three months. This design allowed the researchers to track both clinical trajectories and biological signals as therapy progressed.

At each time point, participants underwent standardized clinical assessments focused on the core features of ME/CFS—fatigue severity, post-exertional malaise, and orthostatic intolerance—using validated patient-reported instruments endorsed by the NIH Common Data Elements for ME/CFS. These measures were selected not to capture vague notions of well-being, but to quantify the symptoms most closely tied to disease burden and daily function.

In parallel, blood samples were collected to examine whether clinical changes were accompanied by shifts in autophagy-related signaling. Rather than surveying hundreds of molecular markers, the investigators focused on two biologically grounded indicators that reflect different steps of the cellular recycling process. BECLIN-1 is a protein required to initiate the formation of autophagosomes—the temporary structures that enclose damaged cellular components so they can be broken down and reused. Phosphorylated ATG13, by contrast, represents a “switched-off” state of an early autophagy protein; when ATG13 is phosphorylated by mTOR, the recycling process is blocked before it can begin.

By tracking both a marker of autophagy initiation and a marker of autophagy inhibition, the researchers could assess not only whether the cleanup machinery was being assembled, but whether it was being allowed to operate. Together, these markers offered a practical window into whether rapamycin was engaging its intended target pathway in living patients.

Importantly, the study was designed to ask a directional biological question, not to establish definitive efficacy. By tracking symptom trajectories alongside autophagy-related biomarkers over time, the researchers sought to determine whether clinical improvement—if observed—would align with restoration of autophagy signaling, rather than occurring independently of it.

This structure reflects a growing shift in translational research for complex chronic illnesses like ME/CFS: away from symptom-first drug trials, and toward mechanism-guided clinical exploration. In this case, rapamycin served not only as a therapeutic candidate, but as a tool to test whether impaired autophagy represents a modifiable vulnerability in ME/CFS biology.

Results

Clinical Response to Low-Dose Rapamycin

To understand how patients responded to rapamycin over time, the researchers followed symptom trajectories across multiple clinical domains rather than relying on a single outcome measure. Although more than one hundred individuals were initially enrolled, not all participants initiated therapy, and—as is common in long, decentralized studies—attrition occurred over time. Forty participants completed the full 90-day protocol, forming the primary “completer” cohort used for longitudinal analysis.

Importantly, weekly low-dose rapamycin was generally well tolerated. Adverse events were infrequent and mild, consisting mainly of transient gastrointestinal symptoms, headaches, or insomnia, most often reported early in the study. These effects tended to diminish with continued treatment, suggesting physiological adaptation rather than cumulative toxicity. When participants discontinued the study, the most common reasons were logistical or financial rather than safety-related—an important consideration for interpreting real-world feasibility.

With tolerability established, the central question became whether modulating mTOR signaling could translate into meaningful improvements in daily function and symptom burden—particularly in the features that define ME/CFS.

Functional Capacity: Gradual Gains in Activity

One of the clearest signals emerged from the Bell Activity Scale, a measure of functional capacity that reflects how much physical and cognitive activity a person can tolerate without triggering symptom worsening. Scores on the scale range from near-complete disability—where individuals are largely confined to bed and unable to perform basic daily tasks—to higher levels of function that allow limited work, household activities, or social engagement without provoking post-exertional malaise.

At baseline, most participants scored in ranges consistent with moderate to severe impairment, meaning that even routine activities such as preparing meals, walking short distances, or concentrating for extended periods could provoke prolonged symptom flares.

Over the course of rapamycin treatment, Bell Activity scores improved gradually but steadily, with the most pronounced gains appearing after three months of therapy. On average, participants experienced an approximately 15% increase in functional capacity—a change that translates not into a return to full health, but into meaningful shifts in daily life, such as greater tolerance for light activity, improved consistency in daily routines, or reduced need for extended recovery after exertion.

Notably, these gains accumulated over time rather than appearing abruptly, a pattern consistent with the idea that restoring autophagy and energy-handling systems may require sustained engagement before functional improvements become apparent.

Core Symptoms: Fatigue, PEM, Sleep, and Orthostatic Intolerance

Improvements were not limited to activity alone. When patients reported on specific ME/CFS symptoms, consistent reductions emerged across all four hallmark features: fatigue, post-exertional malaise, sleep disturbance, and orthostatic intolerance.

Notably, post-exertional malaise—the defining feature of ME/CFS—showed one of the strongest and most sustained improvements. Patients reported that exertion triggered less severe symptom crashes, and that recovery occurred more reliably over time. Improvements in PEM appeared early and persisted across all follow-up time points, suggesting a fundamental shift in how the body responded to energy demand.

Fatigue and sleep quality also improved progressively. At the same time, symptoms related to orthostatic intolerance declined over the treatment period. Orthostatic intolerance refers to the difficulty many ME/CFS patients experience when moving from lying or sitting to standing—a position change that can provoke dizziness, lightheadedness, rapid heart rate, palpitations, blurred vision, or a sense of near-fainting. For some patients, simply standing long enough to prepare a meal, shower, or wait in line can trigger symptoms that force them to sit or lie back down.

Reductions in these symptoms suggest improved tolerance to upright posture and daily transitions—changes that can have an outsized impact on independence and quality of life. Taken together, the parallel improvements in fatigue, PEM, sleep, and orthostatic symptoms indicate that rapamycin’s effects were not narrowly symptomatic, but instead appeared to influence multiple interconnected physiological systems implicated in ME/CFS pathology.

Multidimensional Fatigue: Improvements Across Physical and Cognitive Domains

To capture fatigue more comprehensively, participants also completed the Multidimensional Fatigue Inventory, which separates fatigue into physical, mental, motivational, and activity-related components.

Across nearly all domains, patients reported statistically and clinically meaningful reductions in fatigue. General fatigue declined, but so did physical exhaustion, reduced activity, mental fatigue, and diminished motivation. Importantly, these improvements were not transient: gains observed at earlier time points were largely maintained or strengthened by the end of the 90-day period.

This pattern reinforces the notion that rapamycin was not merely masking symptoms, but may have been addressing a shared upstream driver of fatigue, rather than isolated downstream manifestations.

Taken together, these results suggest that three months of low-dose, once-weekly rapamycin was associated with broad and sustained improvements in ME/CFS symptoms, particularly fatigue, post-exertional malaise, and functional capacity. Improvements unfolded gradually, were observed across multiple validated instruments, and aligned with the core features that define disease severity.

While this observational study cannot establish causality, the consistency of the clinical signal—across activity, fatigue, PEM, autonomic symptoms, and quality of life—sets the stage for the study’s most important question: were these clinical changes accompanied by restoration of autophagy signaling?

That mechanistic link is where the story becomes especially compelling—and where we turn next.

Autophagy as a Biological Signal of Recovery

If rapamycin was truly acting on a core vulnerability in ME/CFS biology—as the investigators hypothesized—then clinical improvement should be accompanied by measurable changes in the cell’s internal repair machinery involved with autophagy. To test this, the researchers tracked two autophagy-related proteins over time: BECLIN-1, a key initiator of autophagosome formation, and phosphorylated ATG13, a modified form of an early autophagy protein whose phosphorylation reflects inhibition of autophagy downstream of mTOR activation.

An autophagosome is a transient, double-membrane vesicle that forms around damaged proteins, dysfunctional mitochondria, and other cellular debris. Once assembled, it delivers this cargo to the lysosome, where the contents are broken down and recycled into usable components. Functionally, autophagosomes act like the cell’s containment and transport system—encapsulating cellular waste so it can be safely processed rather than left to accumulate and interfere with normal operations.

Within this system, BECLIN-1 can be thought of as helping initiate the assembly of these cleanup vesicles, while ATG13 functions closer to an upstream control gate. When ATG13 is phosphorylated by mTOR, that gate remains closed, preventing the recycling process from moving forward. When mTOR activity is reduced, the gate opens, allowing autophagy to proceed.

Together, BECLIN-1 and ATG13 offer complementary insight into whether the cell’s cleanup machinery is being both assembled and permitted to run, rather than stalled partway through the process.

Restoring Autophagy Signaling in the Completer Cohort

Across participants who completed the full 90-day protocol, rapamycin treatment was associated with a progressive rise in BECLIN-1 levels, a pattern consistent with sustained activation of the cell’s recycling machinery rather than a short-lived stress response. 

By the second and third follow-up visits, BECLIN-1 concentrations had increased by roughly 40–50% compared with baseline. In biological terms, this suggests that cells were becoming more capable of assembling autophagosomes—the structures that package damaged components so they can be safely dismantled and reused.

At the same time, the investigators observed a steady decline in phosphorylated ATG13, a molecular signal that reflects when autophagy has been actively suppressed. When ATG13 is phosphorylated by mTOR, the recycling process is effectively paused before it can begin. Over the course of treatment, levels of this inactive form fell consistently, with the largest reductions appearing by the end of the study—more than a two-fold decrease relative to baseline.

This combination is important. An increase in BECLIN-1 alone could reflect cells preparing for cleanup without actually being allowed to proceed. A decrease in phosphorylated ATG13 alone might suggest release of inhibition without effective follow-through. Observing both changes together—more recycling machinery being assembled and fewer molecular signals blocking its activation—indicates that the autophagy process was not just initiated, but increasingly allowed to run.

Taken together, these shifts suggest that rapamycin was doing more than altering protein levels in isolation. It appeared to restore the balance of signals required for effective cellular cleanup, re-engaging a pathway that helps cells recover from stress, clear damage, and maintain energy efficiency—processes that are thought to be compromised in ME/CFS.

Linking Cellular Repair to Symptom Improvement

Crucially, these molecular changes were not isolated laboratory findings. When the investigators examined how shifts in autophagy markers related to patient-reported outcomes, a coherent pattern emerged.

Participants who showed the greatest increases in BECLIN-1 also tended to experience the largest improvements in functional capacity, energy, and overall well-being. Higher BECLIN-1 levels correlated with gains on the Bell Activity Scale and with improvements across multiple quality-of-life domains, including physical functioning, vitality, emotional well-being, and general health. Conversely, rising BECLIN-1 levels were associated with reductions in fatigue severity, including physical fatigue, diminished motivation, and overall fatigue burden.

Reductions in phosphorylated ATG13 showed a more selective association, aligning most strongly with improvements in activity tolerance. This suggests that relieving autophagy inhibition may be particularly important for restoring the ability to engage in daily activity without triggering symptom collapse.

While these associations cannot establish causality, they provide internal biological coherence: clinical improvement clustered with restoration of cellular maintenance pathways.

A Stronger Autophagy Signal in Post-Infectious ME/CFS

The biological signal became even more pronounced when the researchers examined participants whose illness began after a documented viral infection—a subgroup long suspected to represent a distinct biological form of ME/CFS. For these patients, the initial viral stress may have left behind a lasting disruption in how cells manage energy demand and recovery.

In this post-infectious group, rapamycin treatment produced larger and more consistent increases in BECLIN-1, alongside deeper reductions in phosphorylated ATG13 than those observed in the broader cohort. By the end of the study, levels of pSer258-ATG13 had fallen by nearly three-fold, indicating a strong release of mTOR-mediated inhibition of autophagy. In practical terms, this suggests that the cellular recycling machinery in these patients was not only being assembled, but increasingly freed from the signals that normally keep it suppressed.

What makes this finding especially compelling is that these molecular changes were closely mirrored by clinical improvement. Increases in BECLIN-1 tracked with better activity tolerance, higher energy levels, improved emotional well-being, and reductions in fatigue and sleep disturbance. In other words, the patients showing the clearest signs of restored cellular cleanup were also the ones reporting the greatest relief from the symptoms that most limit daily life.

This tight alignment between cellular repair markers and symptom improvement suggests that post-infectious ME/CFS may be particularly responsive to interventions that restore stress-response and repair pathways—perhaps because the initial viral insult created a more specific and persistent block in these systems.

By contrast, participants without a clear viral trigger showed more variable biomarker responses. While this does not rule out benefit in non-viral ME/CFS, the smaller size of this subgroup limits firm conclusions and underscores the need for larger, stratified studies to determine whether different disease origins require different therapeutic strategies.

Autophagy Markers Distinguish Responders from Non-Responders

When participants were stratified by clinical response, autophagy markers again helped distinguish those who improved from those who did not.

Patients classified as responders exhibited the largest increases in BECLIN-1—up to three-fold above baseline—along with early and sustained reductions in phosphorylated ATG13. Partial responders showed intermediate changes, while non-responders exhibited little consistent shift in autophagy markers.

Although not all biomarker–symptom correlations reached significance within these smaller subgroups, the overall pattern reinforced the study’s central hypothesis: clinical improvement clustered with restoration of autophagy signaling.

Safety and Biological Specificity

Because mTOR regulates a wide range of metabolic processes, the investigators also monitored standard laboratory markers throughout the study. Notably, low-dose, once-weekly rapamycin produced no adverse changes in metabolic, hematologic, or lipid parameters over the 90-day period.

This contrasts with the metabolic disturbances reported in studies using high-dose or daily rapamycin. The absence of laboratory abnormalities supports the idea that intermittent mTOR inhibition can selectively engage autophagy without broadly suppressing essential metabolic functions—a distinction with important translational implications.

A Mechanistic Thread Emerges

Taken together, the autophagy biomarker data reinforce the clinical findings. Low-dose rapamycin was associated with:

• suppression of mTOR-dependent autophagy inhibition
• restoration of autophagosome formation
• and molecular changes that tracked with symptom improvement

This matters because these steps represent different stages of the same cellular process. Suppressing mTOR activity removes a signal that normally keeps autophagy turned off; restoring autophagosome formation allows damaged cellular components to be collected; and the alignment of these molecular shifts with symptom improvement suggests that the cleanup process is not merely starting, but progressing in a way that supports recovery from stress.

While this observational study cannot establish cause and effect, it offers rare human evidence linking direct modulation of a conserved cellular maintenance pathway to relief of the symptoms that define ME/CFS. The convergence of clinical improvement and restored autophagy signaling suggests that dysfunction in this pathway may not simply accompany the disease—but may represent a biological vulnerability that can be targeted and potentially corrected.

Discussion: A Mechanistic Signal in a Heterogeneous Disease

ME/CFS has long resisted simple explanations. It lacks objective diagnostic biomarkers, approved therapies, and a unifying pathophysiological model. What has been consistent, however, is the defining vulnerability of patients to exertion—an inability to recover from even modest physical or cognitive demand. This study set out to probe whether that vulnerability might reflect a deeper failure of cellular stress adaptation, and whether restoring one such pathway—autophagy—could translate into clinical benefit.

Building on prior work implicating chronic mTOR activation and impaired autophagy in ME/CFS, the investigators approached rapamycin not as a general immunosuppressant, but as a biological tool: a way to test whether releasing autophagy from inhibition could improve the disease-defining features of fatigue and post-exertional malaise. The results suggest that, at least in a subset of patients, that hypothesis merits serious consideration.

Across participants who completed the study, low-dose, once-weekly rapamycin was associated with broad improvements in fatigue, functional capacity, post-exertional malaise, sleep quality, and orthostatic symptoms—domains that collectively define disease burden in ME/CFS. These improvements were gradual, internally consistent across multiple validated instruments, and not accompanied by adverse metabolic or hematologic effects. Importantly, they were observed without changes in standard metabolic markers, reinforcing the idea that rapamycin’s effects were not mediated by gross metabolic shifts, but by cellular maintenance pathways operating upstream of symptom expression.

What distinguishes this study from prior therapeutic efforts in ME/CFS is the tight alignment between clinical response and molecular evidence of restored autophagy signaling. In participants who improved, BECLIN-1 levels rose and phosphorylated ATG13 levels fell—precisely the pattern expected if mTOR-mediated suppression of autophagy were being relieved. These changes were not merely statistically significant; they tracked with symptom improvement across fatigue, activity tolerance, and quality-of-life measures. In effect, the study offers a rare instance in ME/CFS research where clinical and cellular signals move in the same direction.

In participants who improved, BECLIN-1 levels rose and phosphorylated ATG13 levels fell—precisely the pattern expected if mTOR-mediated suppression of autophagy were being relieved.

The signal was particularly strong among patients whose illness followed a documented viral infection. In this post-infectious subgroup, rapamycin produced deeper and more consistent changes in autophagy markers, alongside greater clinical improvement. While the study was not powered to definitively establish subtype-specific efficacy, the pattern supports a long-suspected idea: that post-infectious ME/CFS may represent a biologically distinct phenotype, characterized by persistent disruption of cellular stress-response pathways.

Taken together, these findings suggest that autophagy dysfunction may not be a downstream consequence of ME/CFS, but a modifiable contributor to its core pathology—particularly in patients whose illness was triggered by viral stress. Rapamycin’s ability to suppress mTOR activity, reduce ATG13 inactivation, and promote autophagosome formation offers a coherent mechanistic explanation for why fatigue and exertional intolerance might improve over time.

At the same time, the study’s limitations must be acknowledged. This was an observational trial without a placebo control, relying on self-reported outcomes rather than objective performance metrics. Attrition was substantial, driven largely by logistical and financial barriers inherent to an unfunded pilot study. Generic variability in rapamycin formulations and unmeasured pharmacokinetic differences likely introduced additional noise. And while within-subject comparisons strengthen internal validity, they cannot fully exclude expectancy effects or regression to the mean.

Importantly, not all participants responded—and the biological data suggest that this heterogeneity is meaningful rather than random. Responders showed the clearest restoration of autophagy signaling; non-responders did not. This distinction underscores a critical lesson for future ME/CFS trials: heterogeneity is not a nuisance variable—it is the signal. Studies that fail to account for underlying biological differences are likely to dilute true effects and produce inconclusive results.

From a translational standpoint, one of the most consequential implications of this work is the potential role of autophagy-related biomarkers as tools for patient stratification. BECLIN-1 and phosphorylated ATG13 are not merely correlates of response; they may help identify, in advance, which patients are biologically positioned to benefit from mTOR-modulating therapies. In a field where “one-size-fits-all” approaches have repeatedly failed, this represents a meaningful shift.

Future studies will need to test these hypotheses under more rigorous conditions: randomized, placebo-controlled designs; standardized drug formulations; pharmacokinetic monitoring; and objective measures of exertional capacity. Incorporating wearable devices, metabolic assays, and longitudinal biomarker profiling could further clarify how cellular repair dynamics translate into day-to-day function. Equally important will be the careful examination of dosing schedules that preserve rapamycin’s ability to engage autophagy without disrupting essential metabolic processes.

In sum, this study does not claim to have solved ME/CFS. What it offers instead is something both more modest and more valuable: evidence that a conserved cellular maintenance pathway—long implicated in aging and stress resilience—can be safely modulated in humans with ME/CFS, and that doing so may alleviate the symptoms that define the disease. If confirmed in larger trials, these findings could mark an important step toward mechanism-guided therapy in a condition that has long lacked both clarity and options.