MicroRNAs mediate dietary-restriction-induced longevity through PHA-4/FOXA and SKN-1/Nrf transcription factors.
MicroRNAs mediate dietary-restriction-induced longevity through PHA-4/FOXA and SKN-1/Nrf transcription factors.
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DOI：
10.1016/j.cub.2014.08.013
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发表时间：
2014-10-06
期刊：
影响因子：
--
通讯作者：
Slack FJ
中科院分区：
文献类型：
--
作者：
Smith-Vikos T;de Lencastre A;Inukai S;Shlomchik M;Holtrup B;Slack FJ
饮食限制（DR）已被证明可以延长不同分类群的寿命，但DR和寿命之间的机制关系仍不清楚。microRNAs（miRNAs）通过调节胰岛素信号、线粒体呼吸和蛋白质稳态中的基因来控制衰老相关的功能，例如代谢和寿命。我们已经开发了与转录因子PHA-4/FOXA和SKN-1/Nrf相关的衰老相关miRNA的网络分析，这两个转录因子都是DR诱导的C寿命延长所必需的。优美的我们的网络分析揭示了PHA-4，SKN-1和miRNA之间广泛的调控相互作用，并指出两个衰老相关的miRNA，miR-71和miR-228，作为这个网络的关键节点。我们发现miR-71和miR-228在C.优美的饮食限制诱导miR-71和miR-228的表达，这些miRNA的调节依赖于PHA-4和SKN-1。反过来，我们发现PHA-4和SKN-1受miR-228负调控，而miR-71抑制PHA-4。根据我们的研究结果，我们发现了饮食限制与衰老之间重要途径的新联系。通过与PHA-4和SKN-1相互作用，miRNAs抑制了饮食限制介导的C.优雅的。考虑到miRNA、PHA-4和SKN-1在胚胎发育中的保守性，这些相互作用可能在更复杂的物种中是保守的。
Dietary restriction (DR) has been shown to prolong longevity across diverse taxa, yet the mechanistic relationship between DR and longevity remains unclear. MicroRNAs (miRNAs) control aging-related functions such as metabolism and lifespan through regulation of genes in insulin signaling, mitochondrial respiration and protein homeostasis. We have developed a network analysis of aging-associated miRNAs connected to transcription factors PHA-4/FOXA and SKN-1/Nrf, which are both necessary for DR-induced lifespan extension in C. elegans. Our network analysis has revealed extensive regulatory interactions between PHA-4, SKN-1 and miRNAs and points to two aging-associated miRNAs, miR-71 and miR-228, as key nodes of this network. We show that miR-71 and miR-228 are critical for the response to dietary restriction in C. elegans. Dietary restriction induces the expression of miR-71 and miR-228, and the regulation of these miRNAs depends on PHA-4 and SKN-1. In turn, we show that PHA-4 and SKN-1 are negatively regulated by miR-228, while miR-71 represses PHA-4. Based on our findings, we have discovered new links in the important pathway connecting dietary restriction to aging. By interacting with PHA-4 and SKN-1, miRNAs transduce the effect of dietary restriction-mediated lifespan extension in C. elegans. Given the conservation of miRNAs, PHA-4 and SKN-1 across phylogeny, these interactions are likely to be conserved in more complex species.
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