Recently, several microRNAs have emerged as potential contributors towards pathways that regulate aging. We have previously shown that miR-228 is required for dietary restriction mediated longevity through interaction with PHA-4 and SKN-1 transcription factors.
mir-229,64,65,66 is a cluster of microRNAs that are in the same family as
mir-228 and share the same human homologs. They are present immediately adjacent to each other on the same chromosome and are thought to share the same promoter and identical seed sequences. Interestingly, we found that in contrast to the anti-longevity role of miR-228, miR-229-66 cluster is required for C. elegans lifespan and longevity observed in
mir-228 mutants. Dietary restriction and reduced insulin signaling up-regulates the expression of miR-229-66 cluster which in turn is critical for the complete extension of lifespan observed under these longevity perturbations. We also show that expression of transcription factors SKN-1 and DAF-16, which are known for their vital role in DR and low IIS mediated longevity, is positively regulated by miR-229-66 cluster. Conversely, these TFs also positively regulate expression of this miRNA cluster, indicating a positive feedback loop essential for longevity. Infact, we observed that miR-229-66 is a requisite for lifespan extension conferred by SKN-1 over expression. Given the conservation of these miRNAs and TFs across species, these interactions are likely to be conserved for longevity in more complex organisms as well.