Abstract
We analyzed the small RNA transcriptome from 5‐month‐old, 24‐month‐old, and 36‐month‐old mouse liver and found 56 miRNAs that changed their expression profile with age. Among these is a cluster of 18 miRNAs that are upregulated between 50‐ and 1,000‐fold at 24 and 36 months of age. This cluster is located in a 60‐kb region of the X‐chromosome that is devoid of other coding sequences and is part of a lamin‐associated domain. Potential targets of the miRNAs in the cluster suggest they may regulate several pathways altered in aging, including the PI3K‐Akt pathway. Total transcriptome analyses indicate that expression of several potential genes in the PI3K‐Akt pathway that may be targeted by the mir‐465 family (mmu‐mir‐465a, mmu‐mir‐465b, and mmu‐mir‐465c) is downregulated with age. Transfection of the liver cell line AML12 with mir‐465 family members leads to a reduction of three of these potential targets at the mRNA level: a 40% reduction of the growth hormone receptor (GHR), and a 25% reduction in Kitl and PPP2R3C. Further investigation of the GHR 3′UTR revealed that the mir‐465 family directly targets the GHR mRNA. Cells transfected with mir‐465 showed a reduction of JAK2 and STAT5 phosphorylation upon growth hormone (GH) stimulation, resulting in a reduction in insulin‐like growth factor 1 (IGF‐1) and IGF‐1‐binding protein 3 expression. With age, GH signaling falls and there is a reduction in circulating IGF‐1. Our data suggest that an increase in expression of the mir‐465 family with age may contribute to the reduction in the GH signaling.
Highlights
Alterations in growth hormone (GH) signaling affect healthspan and lifespan in a wide range of organisms ranging from invertebrates to humans (Bartke, List, & Kopchick, 2016; Barzilai, Huffman, Muzumdar, & Bartke, 2012)
We focused our investigations on the GH receptor (GHR), since the liver is an important site of GH signaling and the GH signaling pathway is known to be involved in the regulation of normal aging
These results indicate that all three mir‐465 family members can target the predicted site in the GHR 3′UTR leading to a reduction in GHR mRNA expression
Summary
Alterations in growth hormone (GH) signaling affect healthspan and lifespan in a wide range of organisms ranging from invertebrates to humans (Bartke, List, & Kopchick, 2016; Barzilai, Huffman, Muzumdar, & Bartke, 2012). Individuals with Laron dwarfism, which results from a mutation in the growth hormone receptor gene, have decreased incidence of diabetes and cancer; they do not have an extended lifespan (Guevara‐Aguirre et al, 2011) Taken together, these results suggest that a reduction in GH signaling has a beneficial effect on healthspan and lifespan. Liver‐specific reduction in IGF‐1 in middle‐aged mice had negative consequences including liver inflammation, accelerated bone loss, oxidative stress in various tissues, and increased hepatic tumors leading to a reduction in healthspan (Gong et al, 2014) These effects are thought to be caused by an increase in circulating GH, resulting from interference with the normal negative feedback loop of IGF‐1 on GH release (List et al, 2014). A reduction in GHR expression will lead to alterations in growth hormone signaling that could affect both healthspan and lifespan
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