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?
Together – TB4/TB-500 + BPC-157 Synergy: