Manni Emad, Jeffery Nicola, Chambers David, Slade Luke, Etheridge Timothy, Harries Lorna W
University of Exeter Medical School, Faculty of Health and Life Sciences, Barrack Road, Exeter EX2 5DW, UK.
Wolfson Centre for Age-Related Diseases, King's College London, London WC2R 2LS, UK.
Exp Gerontol. 2023 Apr;174:112127. doi: 10.1016/j.exger.2023.112127. Epub 2023 Feb 18.
Senescent cells are key regulators of ageing and age-associated disease. MicroRNAs (miRs) are a key component of the molecular machinery governing cellular senescence, with several known to regulate important genes associated with this process. We sought to identify miRs associated with both senescence and reversal by pinpointing those showing opposing directionality of effect in senescence and in response to senotherapy. Cellular senescence phenotypes were assessed in primary human endothelial cells following targeted manipulation of emergent miRNAs. Finally, the effect of conserved target gene knockdown on lifespan and healthspan was assessed in a C. elegans system in vivo. Three miRNAs (miR-5787, miR-3665 and miR-361-5p) demonstrated associations with both senescence and rejuvenation, but miR-361-5p alone demonstrated opposing effects in senescence and rescue. Treatment of late passage human endothelial cells with a miR-361-5p mimic caused a 14 % decrease in the senescent load of the culture. RNAi gene knockdown of conserved miR-361-5p target genes in a C. elegans model however resulted in adverse effects on healthspan and/or lifespan. Although miR-361-5p may attenuate aspects of the senescence phenotype in human primary endothelial cells, many of its validated target genes also play essential roles in the regulation or formation of the cytoskeletal network, or its interaction with the extracellular matrix. These processes are essential for cell survival and cell function. Targeting miR-361-5p alone may not represent a promising target for future senotherapy; more sophisticated approaches to attenuate its interaction with specific targets without roles in essential cell processes would be required.
衰老细胞是衰老和与年龄相关疾病的关键调节因子。微小RNA（miR）是控制细胞衰老的分子机制的关键组成部分，已知有几种miR可调节与该过程相关的重要基因。我们试图通过找出在衰老和对衰老疗法的反应中显示出相反作用方向的miR，来确定与衰老和逆转相关的miR。在对新出现的miRNA进行靶向操作后，评估原代人内皮细胞中的细胞衰老表型。最后，在秀丽隐杆线虫体内系统中评估保守靶基因敲低对寿命和健康寿命的影响。三种miRNA（miR-5787、miR-3665和miR-361-5p）显示出与衰老和年轻化都有关联，但单独的miR-361-5p在衰老和挽救中表现出相反的作用。用miR-361-5p模拟物处理晚期传代的人内皮细胞，导致培养物中衰老负荷降低14%。然而，在秀丽隐杆线虫模型中对保守的miR-361-5p靶基因进行RNA干扰基因敲低，对健康寿命和/或寿命产生了不利影响。尽管miR-361-5p可能会减弱人原代内皮细胞中衰老表型的某些方面，但其许多经过验证的靶基因在细胞骨架网络的调节或形成，或其与细胞外基质的相互作用中也起着重要作用。这些过程对细胞存活和细胞功能至关重要。单独靶向miR-361-5p可能不是未来衰老疗法的一个有前景的靶点；需要更复杂的方法来减弱其与在基本细胞过程中无作用的特定靶点的相互作用。
