I wonder what happens if we combine rapamycin with an IL-11 inhibitor?
I think we all want to see this experiment done, but the ITP wouldnāt use the anti-IL-11 mAb that was already shown to increase mice lifespan, as it almost certainly canāt be effectively administered via chow. The small molecules LMT-28 and FDA-approved bazedoxifene were shown to inhibit IL-11 (+IL-6 in the case of LMT-28), and would be more amenable to testing in the ITP.
Also worth mentioning is the evidence that metformin acts as a TGF-Ī² competitive antagonist, see Metformin is a novel suppressor for transforming growth factor (TGF)-Ī²1. Although metformin failed in the ITP in isolation, metformin+14 ppm rapa from 9 mo may be synergistic in males relative to 14 ppm rapa from 9 mo:
Although the current (C2011) cohort did not contain any mice given Rapa alone, we thought it would be of interest to compare the survival of mice receiving both Rapa and Met to survival of mice treated with the same Rapa dose in previous years, C2006 and C2009 (Miller et al., 2011, 2014). Results are shown in Table S4 (Supporting information). Males given Met/Rapa had a 23% increase in median longevity, higher than the 10% effect produced by Rapa alone in C2006 or the 13% effect in C2009 males. When the results from C2006 and C2009 males were combined for optimal statistical power, and compared with survival in C2011 mice receiving Met/Rapa, the difference did not reach statistical significance (P = 0.12) using our standard calculation, which stratifies by site. An alternate analysis, omitting site stratification, found P = 0.049 for the contrast between Met/Rapa and the historical datasets using Rapa alone at the same dose. Female mice given Met/Rapa also had a higher percentage increase in median lifespan (23%) than females that had received rapamycin alone in the previous C2006 and C2009 cohorts (18% and 21%, respectively), but the difference did not reach significance by logārank testing.
I think we need to clearly distinguish between drugs that directly inhibit TGF-Ī² signaling at the receptor level (e.g RepSox, metformin, circulating Ī±-Klotho), those that directly activate it (e.g rapamycin), those that indirectly modulate it by affecting the levels of bioactive TGF-Ī² (rapamycin also falls into this category), those that modulate downstream pro-fibrotic intracellular signals like SMAD2/3 and YAP/TAZ, as well as those which modulate downstream pro-fibrotic extracellular signals like IL-11.
For example, thereās evidence that SGLT2iās modulate YAP/TAZ signaling and they have anti-fibrotic effects in multiple organs. Empa/cana+rapa+acarb in the 2025 ITP cohort pretty please? 
