Welcome back to Part III. As promised, I’m taking another break (at least on Substack) from politics. However, I cannot move to the science without commenting on the relentless moves by Trump et al, to manipulate, distort, and decimate science by having hyper loyal political appointees decide what research will be funded and what ongoing studies will be terminated.
Please never forget that the deep basic science behind this series on Complex Illness only happens because of funding. We run the real risk of these kinds of basic and translational research projects being shut down prematurely. Which means physicians lose cutting edge interventions and patients will continue to suffer longer.
mTOR, Autophagy, and the Precision Case for Low-Dose Rapamycin
In Part I and Part II, we explored how complex chronic illnesses like ME/CFS and Long Covid are stuck in a cellular lockdown. When an organism is trapped in a chronic Cell Danger Response, the cell behaves like a city under siege. It closes its borders, stops clearing out internal debris, and burns through its localized resources. In our previous deep dives, we looked at how this manifests structurally (the cleavage of SMPDL3B off the immune membrane) and bioenergetically (the WASF3brake on the mitochondria).
Today, we look at the master regulatory switch and nutrient sensing protein behind this entire operation: mTOR (mechanistic target of rapamycin). To appreciate the importance of mTOR, I should point out that it is highly evolutionarily conserved. This means that over the course of millions of years, the protein has survived the selection process of evolution: it is present in all eukaryotes meaning animals, plants, fungi, and yeast. This is a resounding statement regarding its critical role in survival.
By the way, as a lover of science and history, I must also refer you to the very cool story of how rapamycin (sirolimus), found in the dirt on Easter Island, ended up in our arsenal of drugs. It is one of the great sagas in medicine and worth a read: https://fiftytwo.in/story/man-of-culture/
The Cellular Engine: mTORC1 vs. Autophagy
If the Cell Danger Response (CDR) is a stuck firewall, Rapamycin is one of our most promising candidates for a system reboot. To understand why Rapamycin is showing profound promise in complex chronic illnesses like ME/CFS and Long Covid, we have to look at how cells manage their energy economy. As always in nature and our bodies, there is a yin and a yang. Our cells have a dual-mode switch governed by two opposing forces:
mTORC1 (Growth and Defense Mode): When turned ON, it promotes protein synthesis, cell growth, and hyper-vigilant immune activity. It’s an expensive, high-energy state.
Autophagy (The Clean-up Mode): When mTORC1 is turned OFF, the cell enters a self-cleaning cycle. This is our evolved waste management system. It breaks down broken proteins, clears out intracellular pathogens (like persistent viral fragments), and recycles damaged mitochondria (mitophagy).
In a healthy body, this switch flips seamlessly back and forth (except as we age but that is a topic for another day). However, in complex chronic illness, the system gets stuck in a pathological mTOR activation loop. The cell thinks the virus, bacteria, or other toxin is still actively breaking through the gates. It senses danger at the door, and so it keeps the growth/defense engine of mTORC1 revved indefinitely. Anabolic metabolism/protein synthesis, cell growth, and hyperactive immune activity may sound like a good thing, but when it is in constant ON mode, it paradoxically causes adverse effects including chronic smoldering inflammation and all the downstream effects of this. As a side note, in the world of Geromedicine/Geroscience it has been shown that this chronic inflammation causes the diseases of aging: cardiovascular, cancer, and neurodegenerative.
Because the engine never turns off, the clean-up crew (autophagy) never gets deployed. The cellular environment becomes choked with metabolic junk, damaged mitochondria, misfolded proteins, and microbial debris. The cell is hyper-activated, yet utterly exhausted.
The Biochemistry of Dosing: mTORC1 vs. mTORC2
Before we can dive into the utility of rapamycin we again need to look at the yin and yang that is the elegance of evolution.
For decades, medicine knew rapamycin only as an aggressive immunosuppressive drug used in organ transplantation. In fact, the discovery of Rapamycin was the seminal step, after its 1999 approval, in successful organ transplantation. Transplant patients took high, daily doses and organ rejection was vastly reduced. However ( no free lunches in medicine either) in addition to immune suppression, the high doses caused increased risk of infection, insulin resistance, dyslipidemia, mouth ulcers, and impaired wound healing.
Why? Because mTOR exists in two distinct multi-protein complexes:
mTORC1 (The Target): Governs protein synthesis, cell growth, and nutrient sensing. When activated, it suppresses autophagy. Rapamycin binds directly to mTORC1 to turn down this signal, up regulating autophagy.
mTORC2 (The Off-Target Hazard): Governs insulin sensitivity, cell survival, and cytoskeletal organization. Rapamycin does not directly bind mTORC2. However, chronic, daily high-dose exposure slowly starves the cell of the raw mTOR molecules needed to form complex 2, leading to mTORC2 disruption and rising glucose and lipids.
Rapamycin: The Dosing Paradox
Why would we use a powerful immune suppressing drug to treat our patients with chronic complex illness, especially since many already have impaired immune competence and reactivated infections? As so often is the case in medicine, the answer is the dose.
Instead of high daily dosing of rapamycin, a low once weekly dose has the complete opposite effect. Far from suppressing the immune system, Dr. Joan Mannick’s landmark studies showed that low-dose, intermittent mTOR inhibition in older adults actually enhanced immune competence, up-regulated antiviral gene expression, and boosted vaccine response titers. We aren’t knocking out the immune system; we are recalibrating a hyper-fatigued host response.
By briefly inhibiting mTORC1, once a week, low-dose Rapamycin flips the switch and up regulates autophagy. It provides a signal to the cell and breaks the counterproductive defensive cycle the cell has been stuck in: The siege is over. Clean the house.
The Clinical Pivot:
In treating these fragile systems, the dosing paradigm is everything. We are not suppressing the immune system; we are utilizing a highly evolved biologic process. A single weekly dose creates a transient dip in mTORC1, long enough to trigger autophagy without impacting TORC2 and the related adverse effects. And because the half life of rapamycin is about 65 hours, the TORC1 inhibition is transient and the cell is restored to the normal cycling of anabolic and catabolic metabolism.
Rapamycin may not be the silver bullet for chronic complex illness. Bu it is a potent, precise instrument, another critical tool in our toolbox. The unregulated autophagy initiates a deep cellular housecleaning, with clearance of viral debris and metabolic junk. Mitochondrial bioenergetics improve. Systemic inflammation (muscle, organ, and brain) decreases with a corresponding decrease in symptoms.
From Bench to Bedside: BECLIN-1 and pSer258-ATG13
Let’s circle back to where we started. Basic science, bench science drives progress in medicine.
Heterogeneity has always been the single biggest obstacle in chronic illness trials. Without actionable biomarkers, “fatigue trials” mix responsive patients with non-responsive ones, diluting clinical signals.
In our recent published trials with Dr. Gunnar Gottschalk and the Simmaron Research team, we set out, among other things, to prove that we could track and predict autophagy restoration in real time.
The Molecular Lock (pSer258-ATG13) and Baseline Biomarker
Bear with me as I dive into more biochemistry.
We identified that hyper-active mTORC1 phosphorylates the early autophagy protein ATG13 at Serine-258. This specific phosphorylation event physically dislodges ATG13, trapping the cell in an autophagy-blocked state. In mouse models, genetic ablation or inactivation of ATG13 induces severe exercise-induced muscle fatigue—the exact biological mirror of Post-Exertional Malaise (PEM). Bingo! Talk about Bench to Bedside, Translational Medicine.
This research laid the groundwork for two open label (non placebo) clinical trials prescribing rapamycin to people with ME/CFS and Long Covid.
In both trials we found that 6mg of rapamycin pulsed weekly selectively suppressed mTORC1 without triggering mTORC2 side effects. Over 70% of participants completing the protocol showed significant recovery in fatigue and PEM scores on multiple validated questionnaires. In the laboratory, we observed a more than two-fold reduction in phosphorylated pSer258-ATG13 alongside a marked upregulation in another molecule, BECLIN-1. A key driver of autophagosome formation, Beclin-1 marks the up regulation of autophagy and the down regulation of inflammation. Basic science at work.
A Potential Biomarker
Elevated baseline levels of inactive pSer258-ATG13 give us a rational, targetable biomarker. Instead of blindly prescribing, we can potentially identify the exact subset of ME/CFS and Long Covid patients whose symptoms are driven by mTOR-mediated autophagy blockade. Furthermore, we can measure their biological recovery as BECLIN-1 rises and pSer258-ATG13 drops, correlating subjective symptom improvement with objective biomarkers. These tools may also allow us to personalize the dosing for each patient. While the weekly 6mg dose is an initial target dose, we have learned that some patients, based on their symptoms and response, need lower doses, higher doses, or even multiple doses during the week.
Clinical Summary
So let’s try to summarize why we are so excited about rapamycin. What does it do? Hopefully this brief list is helpful.
Autophagy: a highly conserved housekeeping waste management biologic process that recycles metabolic waste and damaged organelles via lysosomal degradation. This “cleans the system” while also providing recycled molecules for new synthesis of proteins.
Xenophagy/Debris Clearance: Upregulated autophagy also clears foreign proteins including viral proteins and other intracellular pathogens. This degradation process helps expose microbial antigens to the immune system for further infection control.
Mitophagy: Clears damaged mitochondria including those with dysfunction in the electron transport chain. This helps improve healthy mitochondrial biomass and restore more efficient ATP synthesis. Increased ATP (fuel) improves bioenergetics leading to decreases in both fatigue and PEM.
Neuroinflammation: TORC1 inhibition can decrease microglial activation in the brain. This leads to decrease in the neuroinflammation associated with the symptoms of brain fog and sensory hypersensitivity.
We are not attempting to shut down immune responses with a high-dose transplant medicine; we are utilizing an intermittent, low-dose molecular pulse. By sparing mTORC2, we avoid metabolic toxicity while restoring the cell’s ancient capacity to clean house, repair damaged energy pathways, and break free from the Cell Danger Response.
We hope to begin a full Randomized Placebo Controlled trial to further prove these findings. Sadly, the only thing holding back this next step is funding. But regardless of whether we can move forward with this RCT, I and many other physicians will continue to prescribe low dose rapamycin based on the current experience and data.
As the basic science matures, the clinical reality is becoming undeniable: by understanding the master switches like mTOR, we are no longer just guessing in the dark. We are actively learning how to reach into the jammed machinery of the cell, throw the circuit breakers, and and help the system reboot itself.
Additional notes and references:
You can hear me discuss this research directly with my co-investigator Dr. Gunnar Gottschalk, on the ME/CFS, Long Covid, and Rapamycin Podcast. This discussion walks through the trial design and explains how targeting autophagy pathways could transform chronic illness care.
In the interest of full transparency, please know that I used AI for some of the research for and organization of this post.
Below are some selected references:
mTOR inhibition improves immune function in the elderly https://pubmed.ncbi.nlm.nih.gov/25540326/
Association of rapamycin treatment with the modulation of purine metabolism, reduced microglial inflammatory responses, improved mitochondrial energy metabolism, and alleviation of fatigue symptoms in ME/ CFS subjects: pilot findings from phase-II observational study
https://link.springer.com/article/10.1186/s12967-026-08575-3
Low-dose rapamycin alleviates clinical symptoms of fatigue and PEM in ME/CFS patients via improvement of autophagy: a pilot study
https://pmc.ncbi.nlm.nih.gov/articles/PMC12538759/
Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of receptor for advanced glycation end products (RAGE). Mol Cell Neurosci. 2022;120:103731.
Inactivation of ATG13 stimulates chronic demyelinating pathologies in muscle-serving nerves and spinal cord. Immunol Res. 2025;73:27