mTORC1, Autophagy, and Rapamycin in ME/CFS

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This discussion is an extension of the previously described in summary the consequences of chronic mTOR activation in Chronic activation of the mTOR pathway has significant implications for cellular and organismal health: previous article on chronic mTOR activation.

At the Community Symposium on the Molecular Basis of ME/CFS, on 9/11/2026, David Kaufman presented a proposed connection between mTORC1 activation, impaired autophagy, mitochondrial dysfunction, inflammation, and ME/CFS, together with the possibility of using rapamycin (sirolimus) to modify this pathway.

mTORC1 and autophagy

mTORC1 is an important cellular sensor of nutrients, energy availability, growth signals, and stress. When mTORC1 is active, it promotes growth and protein synthesis while suppressing autophagy.

Autophagy is the cell's recycling and quality-control system:

Damaged proteins/mitochondria → autophagosome → lysosome → degradation → recycling

A particularly important component is mitophagy, which removes damaged mitochondria. Kaufman's model proposes that persistently increased mTORC1 activity could suppress this cellular cleanup system, resulting in accumulation of damaged mitochondria and other cellular material. The presentation connects this with increased inflammatory signaling, impaired immune and viral clearance, chronic immune activation, autoimmunity, and altered T-cell metabolism.

The proposed pathway can therefore be summarized as:

↑ mTORC1 → ↓ autophagy/mitophagy → damaged mitochondria and cellular waste → metabolic + inflammatory/immune dysfunction → possible contribution to ME/CFS

Rapamycin as a possible intervention

Rapamycin (sirolimus) inhibits mTORC1 and can promote autophagy. The therapeutic hypothesis is therefore:

Rapamycin → ↓ mTORC1 → ↑ autophagy → improved cellular recycling

Rather than continuous mTOR suppression, Kaufman's presentation proposes intermittent treatment—a "molecular pulse" intended to temporarily inhibit mTORC1 and activate cellular recycling. This is conceptually different from chronic immunosuppressive rapamycin treatment.

The presentation describes an uncontrolled decentralized study of 86 people with ME/CFS receiving rapamycin 6 mg/week. Among 70 participants included in the reported outcome analysis, 52 (74.3%) showed improvement/recovery in fatigue, PEM and/or orthostatic-intolerance measures. No serious adverse events were reported. Because there was no randomized control group, these findings should be considered a preliminary clinical signal rather than evidence that rapamycin is an effective ME/CFS treatment.

Measuring the proposed mechanism

The presentation identifies ATG13 as a potential marker associated with impaired autophagy and Beclin-1 with active autophagy. The reported rapamycin observations showed decreased ATG13 and increased Beclin-1, consistent with the proposed mechanism.

An even more informative research approach may be to measure autophagic flux directly. This can be investigated in peripheral blood mononuclear cells (PBMCs) by measuring LC3B-II before and after lysosomal inhibition:

Autophagic flux ≈ LC3B-II (lysosome inhibited) − LC3B-II (control)

This dynamic measurement can distinguish increased production of autophagosomes from their accumulation because degradation is impaired. ATG13 and PBMC LC3B-II autophagic-flux assays, however, remain primarily research methods rather than established clinical tests for ME/CFS.

Overall, this work extends the earlier discussion of the potential consequences of chronic mTOR activation by proposing a specific ME/CFS mechanism linking mTORC1 → impaired autophagy → mitochondrial and immune dysfunction, along with biomarkers that could potentially test the hypothesis and rapamycin as an experimental means of modifying the pathway.

References:

Cell‐Type‐Specific Autophagy in Human Leukocytes
https://pmc.ncbi.nlm.nih.gov/articles/PMC12159969/?utm_source=chatgpt.com

Measurement of autophagic flux from human peripheral blood mononuclear cells in health and cardiometabolic disease
https://journals.physiology.org/doi/abs/10.1152/physiol.2026.41.S1.2344294?utm_source=chatgpt.com

Measurement of Physiological Autophagic Flux in the Human Peripheral Blood Mononuclear Cell Pool
https://pubmed.ncbi.nlm.nih.gov/41082113/

© 2000-2030 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9


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