miR-124/ATF-6, a novel lifespan extension pathway of Astragalus polysaccharide in Caenorhabditis elegans.

MicroRNAs (miRNAs), especially evolutionarily conserved miRNAs play critical roles in regulating various biological process. However, the functions of conserved miRNAs in longevity are still largely unknown. Astragalus polysaccharide (APS) was recently shown to extend lifespan of Caenorhabditis elegans, but its molecular mechanisms have not been fully understood. In the present study, we characterize that microRNA mediated a novel longevity pathway of APS in C. elegans. We found that APS markedly extended the lifespan of C. elegans at the second and the fourth stages. A highly conserved miRNA miR-124 was significantly upregulated in APS-treated C. elegans. Overexpression miR-124 caused the lifespan extension of C. elegans and vice versa, indicating miR-124 regulates the longevity of C. elegans. Using luciferase assay, atf-6 was established as a target gene of miR-124 which acting on three binding sites at atf-6 3'UTR. Consistently, agomir-cel-miR-124 was also shown to inhibit ATF-6 expression in C. elegans. APS-treated C. elegans showed the down-regulation of atf-6 at protein level. Furthermore, the knockdown of atf-6 by RNAi extended the lifespan of C. elegans, indicating atf-6 regulated by miR-124 contributes to lifespan extension. Taken together, miR-124 regulating ATF-6 is a new potential longevity signal pathway, which underlies the lifespan-extending effects of APS in C. elegans.