The regulation of Insulin/IGF-1 signaling by miR-142-3p associated with human longevity

Author:

Wang Xifan,Jung Hwa Jin,Milholland Brandon,Cui Jinhua,Tazearslan Cagdas,Atzmon Gil,Wang Xizhe,Yang Jiping,Guo Qinghua,Barzilai Nir,Robbins Paul D.,Suh Yousin

Abstract

AbstractMicroRNAs (miRNAs) have been demonstrated to modulate life span in the invertebratesC. elegansandDrosophilaby targeting conserved pathways of aging, such as insulin/IGF-1 signaling (IIS). However, a role for miRNAs in modulating human longevity has not been fully explored. Here we investigated novel roles of miRNAs as a major epigenetic component of exceptional longevity in humans. By profiling the miRNAs in B-cells from Ashkenazi Jewish centenarians and 70-year-old controls without a longevity history, we found that the majority of differentially expressed miRNAs were upregulated in centenarians and predicted to modulate the IIS pathway. Notably, decreased IIS activity was found in B cells from centenarians who harbored these upregulated miRNAs. miR-142-3p, the top upregulated miRNA, was verified to dampen the IIS pathway by targeting multiple genes includingGNB2, AKT1S1, RHEBandFURIN. Overexpression of miR-142-3p improved the stress resistance under genotoxicity and induced the impairment of cell cycle progression in IMR90 cells. Furthermore, mice injected with a miR-142-3p mimic showed reduced IIS signaling and improved longevity-associated phenotypes including enhanced stress resistance, improved diet/aging-induced glucose intolerance, and longevity-associated change of metabolic profile. These data suggest that miR-142-3p is involved in human longevity through regulating IIS-mediated pro-longevity effects. This study provides strong support for the use of miR-142-3p as a novel therapeutic to promote longevity or prevent aging/aging-related diseases in human.

Publisher

Cold Spring Harbor Laboratory

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