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Long‐lived mutant mice, both Ames dwarf and growth hormone receptor gene–disrupted or knockout strains, exhibit heightened cognitive robustness and altered IGF1 signaling in the brain. Here, we report, in both these long‐lived mice, that three up‐regulated lead microRNAs, miR‐470, miR‐669b, and miR‐681, are involved in posttranscriptional regulation of genes pertinent to growth hormone/IGF1 signaling. All three are most prominently localized in the hippocampus and correspond to reduced expression of key IGF1 signaling genes: IGF1, IGF1R, and PI3 kinase. The decline in these genes’ expression translates into decreased phosphorylation of downstream molecules AKT and FoxO3a. Cultures transfected with either miR‐470, miR‐669b, or miR‐681 show repressed endogenous expression of all three genes of the IGF1 signaling axis, most significantly IGF1R, while other similarly up‐regulated microRNAs …