Molecular Entomology 2024, Vol.15, No.1, 18-22 http://emtoscipublisher.com/index.php/me 19 Figure 2 Trametinib decreases aging-associated gut pathology in females, effect of trametinib on ISC proliferation, gut pathology, and barrier function in females and males Figure 4 demonstrates that Trametinib reduces Pol III activity by decreasing the levels of precursor tRNAs. in Part A, Trametinib-fed female holoblast Drosophila have significantly lower levels of pre-tRNAHis, pre-tRNAIle, and pre-tRNALeu compared to DMSO controls. In Part B, the survival curves of Trametinib-fed Dole 3D mutant female Drosophila show significantly longer lifespans compared to controls, but do not show an additive effect when the two are combined.Part C notes that Trametinib similarly reduces the expression of these three precursor tRNAs in intestinal tissues.Part D uses FACS to isolate the three precursor tRNAs from esg-gal4 > GFP Drosophila isolates exhibit the same trend of precursor tRNA reduction.Part E shows that specific induction of Polr3D RNAi in ISCs extends Drosophila lifespan and is not additive to the life-extending effect of Trametinib.Part F shows that knockdown of 5961-GS > Maf1RNAi in Drosophila induced by RU486 does not affect lifespan. Maf1 did not affect lifespan but significantly reduced the life-extending effect of Trametinib. These results suggest that Trametinib may exert its anti-aging effects by affecting Pol III activity and related factors. Figure 5 demonstrates the mechanism of action of Trametinib in intestinal stem cells (ISCs) to extend lifespan through the Ras/MAPK-Maf1-Pol III axis.Trametinib reduces phosphorylated ERK (pERK) levels through inhibition of MEK, which in turn reduces phosphorylation of Maf1.The reduction in phosphorylation of Maf1 results in a greater presence of the cell nucleus which inhibits the transcriptional activity of Pol III and reduces tRNA synthesis. This series of reactions ultimately leads to reduced epithelial dysplasia and tumor formation in older Drosophila, reduced intestinal barrier dysfunction, and reduced risk of death, which has a positive effect on extending the lifespan of female Drosophila. Through this mechanism, Trametinib demonstrates its potential in delaying aging.
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