TGF-β signaling and rapamycin

I was working on this draft for some time and then I accidentally posted it, so I’m just going to go ahead and leave it as is. I used ChatGPT to format the bold font, but the content is not AI generated.

Introduction to TGF-β: A Double-Edged Regulator of Aging

Although it hasn’t yet gained the attention of the classical nutrient sensing pathways (e.g mTORC1, AMPK, Insulin/IGF-1, etc), the TGF-β pathway is a potential dark horse in the aging process. Upon ligand binding, TGF-β receptors activate the SMAD2/3 transcription factors, which translocate to the nucleus and regulate the expression of numerous genes.

The Dark Side: TGF-β as an Anti-Longevity Factor

TGF-β is widely recognized as the master regulator of fibrosis [1]—a pathological tissue remodeling process that can occur across organs, particularly the liver, lungs, kidneys, and heart. Fibrotic disease is a major contributor to mortality, with U.S. government estimates attributing up to 45% of deaths to fibrotic complications. Central to this mechanism is TGF-β–induced activation of interleukin-11 (IL-11), which appears to be its dominant downstream transcriptional target [2]. IL-11 is not only required for TGF-β-driven fibrosis, but has also been implicated in regulating mammalian lifespan [3] and promoting cancer [4].

Furthermore, recent studies reveal that TGF-β accelerates epigenetic aging by directing chromatin remodeling along pro-aging trajectories [5]. In this context, TGF-β functions as an anti-longevity factor , contributing to multiple hallmarks of aging—most notably epigenetic alterations and the recently recognized hallmark of extracellular matrix (ECM) changes .

The Flip Side: Immunoregulation and Tumor Suppression

Despite its pathological roles, TGF-β also acts as a crucial anti-inflammatory and immunoregulatory agent. It inhibits pro-inflammatory cytokine production and activates regulatory T cells (Tregs), playing a central role in immune tolerance. Its systemic importance is underscored by the observation that TGF-β1 knockout mice die by postnatal day 20 due to uncontrolled inflammation and autoimmunity [6] [7].

Moreover, TGF-β exhibits context-dependent tumor suppressive functions, especially during early carcinogenesis. However, this protective role reverses in later stages, where TGF-β promotes metastasis—the leading cause of cancer-related mortality.

Move aside mTORC2: is TGF-β the hidden off-target of rapamycin?

While it’s widely recognized that rapamycin inhibits mTORC1, relatively little attention has been given to the evidence suggesting that it also modulates TGF-β signaling, adding a complex layer to its pharmacology. Depending on the system and duration of exposure, rapamycin can either increase or decrease TGF-β protein levels and mRNA expression [8] [9] [10] [11] [12].

Rapamycin also directly increases TGF-β signaling by binding to FKBP12, a protein that normally stabilizes the inactive conformation of the TGF-β type I receptor (TGFBRI). By sequestering FKBP12, rapamycin can disinhibit TGFBRI, leading to ligand-independent (constitutive) activation of the TGF-β pathway [13]. As a relevant aside, FKBP12 is also required for rapamycin-mediated inhibition of mTORC2 . Tissues with low FKBP12 expression—such as the thymus, kidney, and stomach —are rendered insensitive to mTORC2 inhibition by rapamycin [14]. Another study reports that rapamycin activates TGF-β signaling by inducing reactive oxygen species (ROS), which enhance SMAD2/3 phosphorylation—a process that can be attenuated with N-acetylcysteine (NAC) [15]. This raises the intriguing possibility of rapamycin+NAC synergy.

Unsurprisingly, rapamycin’s activation of TGF-β signaling can amplify pathological processes in certain contexts, including fibrosis, inflammation, and organ-specific dysfunction [16] [17] [18] [10] [20]. However, this is modulated by its concurrent inhibition of mTOR, which often exerts protective effects and mitigates these risks [21] [22] [23] [24] [25] [26] [27] [28] [29] [30].

Given these dual and sometimes opposing effects, it is imperative to dissociate the benefits of mTORC1 inhibition from the potentially deleterious effects of TGF-β activation. Could allosteric mTORC1 inhibitors —designed to stabilize its inactive conformation , bypass FKBP12 , and thereby avoid unintended activation of TGF-β signaling —offer superior longevity benefits compared to rapamycin? Might a combination of rapamycin with anti–IL-11 therapy unlock a new synergy, assuming IL-11 mediates the most deleterious effects of TGF-β? Or, counterintuitively, could TGF-β activation by rapamycin play a nuanced and beneficial role in its overall anti-aging efficacy?

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This is great! I have been meaning to research this for quite some time and really appreciate your effort here

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I wonder if any of the many transplant patients who have taken Rapamycin have Marfans Syndrome or other conditions in which TGF beta is an issue. Do these people have problems, or do they fare well.

I was interested in TGF-β 's link to splicing so I asked chatGPT and got this response

It strikes me that the core issue is the differential splicing of its targets. I am therefore not persuaded that there is any need to try to intervene in TGF β itself

I also asked about Marfan syndrome

This may be an area where any direct affect of rapamycin may help, but ordinarily I would expect rapamycins role to primarily relate to improved splicing

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Telmisartan is thought to affect TGF beta in a favorable way. Perhaps a Telmisartan/ Rapamycin combo would be synergistic.

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