新成果!靶向关键基因,或可逆转细胞衰老
2018/09/23
衰老是一个自然而然的过程,但是伴随着衰老进程,很多疾病(包括痴呆、癌症)的发生概率会显著增加。所以,科学家们一直试图减缓甚至于逆转这一过程。近日,《The FASEB Journal》期刊发表了一项最新研究,揭示了或可实现细胞衰老逆转的关键因子。


图片来源:CC0 Public Domain

这一研究由埃克塞特大学医学院的科学家们完成。他们发现,某些调控剪接因子(splicing factors)的基因和通路在细胞衰老过程中起着关键作用。更重要的是,他们证实,扰乱这一遗传过程,有望逆转细胞衰老。

先前已有研究表明,细胞老化是机体衰老的驱动因素,在动物模型中去除这些细胞,衰老的许多特征可以被逆转。

现在,文章作者、埃克塞特大学医学院的Lorna Harries及其团队发现,抑制ERK和 AKT(传递胞外信号、影响基因表达)的通路,能够减少衰老细胞的数量。此外,敲除这两个通路调控的两个基因——FOX01、ETV6同样可以减少衰老。


https://doi.org/10.1096/fj.201801154R

最新研究表明,ERK和 AKT通路激活可能会阻碍剪接因子的活性,从而导致衰老细胞堆积。所以,为了抑制ERK和AKT通路的活性,研究团队选用了已在临床中作为抗癌药物的抑制剂。

当通路被药物阻止后,研究人员发现剪接因子水平增加。这意味着,蛋白质和基因之间有更好的交流。与此同时,衰老细胞数量也在减少。他们发现,衰老细胞身上与衰老过程有关的许多特征发生了逆转,导致细胞再生。

“我们很兴奋于这样的发现——干扰目标基因至少可以部分逆转人类细胞衰老过程中的关键因素。这一发现有助于我们找到延缓细胞衰老的方法,从而避免一些因细胞衰老而引发的疾病,例如痴呆症和癌症。” Lorna Harries表示,“我们选用的化合物已经广泛应用于抗癌治疗中,所以相对安全。但是这项研究还处于早期阶段,下一步我们需要深入解析细胞和遗传物质影响机体衰老的机制。”

责编:风铃

参考资料:

Disrupting genetic processes reverses ageing in human cells

FOXO1 and ETV6 genes may represent novel regulators of splicing factor expression in cellular senescence

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  • FOXO1 and ETV6 genes may represent novel regulators of splicing factor expression in cellular senescence

    Cellular plasticity is a key facet of cellular homeostasis requiring correct temporal and spatial patterns of alternative splicing. Splicing factors, which orchestrate this process, demonstrate age-related dysregulation of expression; they are emerging as potential influences on aging and longevity. The upstream drivers of these alterations are still unclear but may involve aberrant cellular signaling. We compared the phosphorylation status of proteins in multiple signaling pathways in early and late passage human primary fibroblasts. We then assessed the impact of chemical inhibition or targeted knockdown of direct downstream targets of the ERK and AKT pathways on splicing factor expression, cellular senescence, and proliferation kinetics in senescent primary human fibroblasts. Components of the ERK and AKT signaling pathways demonstrated altered activation during cellular aging. Inhibition of AKT and ERK pathways led to up-regulation of splicing factor expression, reduction in senescent cell load, and partial reversal of multiple cellular senescence phenotypes in a dose-dependent manner. Furthermore, targeted knockdown of the genes encoding the downstream targets FOXO1 or ETV6 was sufficient to mimic these observations. Our results suggest that age-associated dysregulation of splicing factor expression and cellular senescence may derive in part from altered activity of ERK and AKT signaling and may act in part through the ETV6 and FOXO1 transcription factors. Targeting the activity of downstream effectors of ERK and AKT may therefore represent promising targets for future therapeutic intervention.—Latorre, E., Ostler, E. L., Faragher, R. G. A., Harries, L. W. FOXO1 and ETV6 genes may represent novel regulators of splicing factor expression in cellular senescence.

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