Stabilisation of extracellular matrix is crucial to rapamycin-mediated life span increase in Marfan mgR/mgR mice
Marfan syndrome is a hereditary connective tissue disorder caused by heterozygous mutations in the fibrillin-1 gene (FBN1) and altered TGF-β signalling. Life-threatening complications involve thoracic aortic aneurysms (TAA) and dissections due to the disruption of microfibrillar assembly in the aortic wall. We previously demonstrated that Rapamycin, a typical mTOR pathway inhibitor, limits the ascending aorta elastolysis and expansion, significantly increasing lifespan in an established murine model of Marfan syndrome (Zaradzki et al., Biochem Pharmacol 2022).
This study aimed to investigate how mTOR inhibition stabilises the aorta in fibrillin-1 hypomorphic mgR/mgR mice and previously observed increased life expectancy. We used antibody microarrays to detect protein expression in the proximal thoracic aorta of sham or rapamycin-treated male and female mgR/mgR mice immediately after the two-week treatment. Immunofluorescence staining was performed to visualize and quantify protein expression in the ascending thoracic aorta and arch four weeks after the short-term rapamycin treatment was completed.
We showed that rapamycin significantly increased the abundance of extracellular matrix (ECM) proteins like cytokeratin-18 and betaglycan, also known as the TGF-β type 3 receptor (TGFBR3). In addition, it raises the abundance of aggrecanase-2 (ADAMTS5) and xylosyltransferase-1 proteins, enzymes involved in ECM remodelling and homeostasis.
In conclusion, rapamycin affects the composition and organization of key ECM components, which determine the structure–function relationships in the aorta, thereby maintaining the balance critical for the increase in life expectancy. Using mTOR modulators for targeted therapy may help to prevent aortic complications of MFS and improve clinical outcomes.
I doubt it has much relevance for healthy mammals. The mice in this study had Marfan disease, which causes a lot of problems that have little in common with normal aging. These mice have elevated TGF-beta and rapamycin is known to decrease TGF-beta, so maybe the rapamycin is mostly helping correct some of the problems related to this desease specifically rather than doing anything that would be beneficial for general aging.
Do you have a source for this? I have a number of paper showing rapamycin can increase or decrease TGF-β transcription or protein levels depending on system and duration of exposure. [1][2][3][4][5]. I don’t think it’s at all clear that rapa decreases TGF-β levels.
Furthermore, rapamycin’s ligand FKBP12 stabilizes inactive conformation of the TGFBR1, so by sequestering FKBP12, rapamycin can constitutively activate the TGF-β pathway. There’s a lot of papers examining this link between FKBP12 and TGFBR1, and it has specifically been demonstrate with rapamycin. [6]
This is a concern, given the high mechanistic plausibility that TGF-β is a gerogene. I think it’s quite likely FKBP12-independent mTORC1 selective allosteric inhibitors would be superior, especially when you consider the role that FKBP12-binding plays in mTORC2 inhibition. [7]
Thanks for the reply and references. I mixed things up a bit. Going by memory I thought I had seen clear evidence that rapamycin inhibits TGF-beta, but when I checked some of the studies I had saved on that I realized that I was thinking of studies that showed that rapamycin inhibits the downstream pathways of TGF-beta, not TGF-beta directly. As you correctly point out, and the references you gave indicate, it’s not so clear what effects rapamycin has on TGF-beta, and it might even increase it in some contexts. It still seems to reduce some of the effects of TGF-beta.
Note that TGF-beta is a growth factor so it makes sense that maybe it’s acting partially through mTOR in which case inhibiting mTOR would prevent some of the downstream effects of TGF-beta activation. This appears to be the case. Studies show that mTOR inhibition can potentially inhibit the increase in extracellular matrix synthesis (such as collagen deposition and fibrosis) in response to TGF-beta activation. (1)(2)(3)(4)(5)
This is something I came across when I was looking for treatments for Dupuytren’s disease, which is a disease caused in part by increased TGF-beta and associated excessive extracellular matrix growth. Interestingly, there was a person on this forum whose Dupuytren disease partially reversed when he started taking rapamycin.
