Petrashen Anna P, Lin Yufei, Kun Bianca, Kreiling Jill A
Department of Molecular Biology, Cell Biology and Biochemistry, Center for the Biology of Aging, Brown University, Providence, RI, United States.
Front Aging. 2023 Oct 10;4:1261121. doi: 10.3389/fragi.2023.1261121. eCollection 2023.
Growth hormone (GH) signaling influences lifespan in a wide variety of mammalian species. We previously reported that a cluster of miRNAs located on the X-chromosome are de-repressed with age in male mouse liver, and a subset, the mir-465 family, can directly attenuate expression of the growth hormone receptor (GHR) leading to a reduction in GH signaling. Here we show that this cluster of miRNAs is also upregulated in the liver with age in females, and that calorie restriction and the Ames dwarf genotype, both known to delay aging, attenuate the upregulation of the miRNA cluster. Upregulation of mir-465 leads to a reduction in GHR mRNA in the liver and an attenuation of GH signaling, indicated by a reduction in GHR, IGF-1, IGFBP3, and ALS mRNA expression. There is a corresponding reduction in IGF-1 protein levels in the liver and plasma. These results suggest that the age-associated upregulation of the X-chromosomal cluster of miRNAs could influence lifespan.
生长激素（GH）信号传导影响多种哺乳动物的寿命。我们之前报道过，位于X染色体上的一组微小RNA（miRNA）在雄性小鼠肝脏中会随着年龄增长而解除抑制，其中一个子集，即mir-465家族，可直接减弱生长激素受体（GHR）的表达，导致GH信号传导减少。在此我们表明，这组miRNA在雌性肝脏中也会随着年龄增长而上调，并且已知能延缓衰老的热量限制和艾姆斯侏儒基因型会减弱miRNA簇的上调。mir-465的上调导致肝脏中GHR mRNA减少以及GH信号传导减弱，这表现为GHR、IGF-1、IGFBP3和ALS mRNA表达降低。肝脏和血浆中的IGF-1蛋白水平相应降低。这些结果表明，与年龄相关的X染色体miRNA簇上调可能会影响寿命。
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