Abstract

Telomere shortening in neural stem cells is considered a key mechanism in brain aging. The search for ways to lengthen telomeres in neural stem cells appears to be a promising research direction in neuromedicine. Approaches based on increasing the expression of telomerase in stem cells have failed because of higher risk of tumorigenesis which accompanies high levels of telomerase expression. We propose another, fundamentally different, strategy to increase telomerase activity by excluding alternative splicing. It has been shown that out of 22 splice variants of telomerase only one has telomerase activity, while the other variants of this enzyme are capable of inhibiting it, and at the same time, promote cancer. We suggest editing the gene of telomerase in a way that increases the efficiency of telomere lengthening by excluding alternative splicing. This mechanism of enhancing telomerase activity will maintain telomerase expression at the safe level and will exclude a higher risk of carcinogenesis. It is hypothesized, that editing the telomerase gene in neural brain stem cells can increase neurogenesis effectivity in the adult brain, and slow down the changes in nerve activity. Further research can lead to the potential development of gene therapy that could slow down the aging process in the brain.

中文翻译：

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体内神经干细胞中端粒酶基因编辑作为一种可能的抗脑衰老新方法

摘要

神经干细胞中端粒的缩短被认为是大脑衰老的关键机制。在神经干细胞中寻找延长端粒的方法似乎是神经医学的有前途的研究方向。基于增加端粒酶在干细胞中表达的方法失败了，因为伴随高水平端粒酶表达的更高的致癌风险。我们提出了另一种根本不同的策略，即通过排除其他剪接来增加端粒酶活性。已经表明，在22个端粒酶剪接变体中，只有一个具有端粒酶活性，而该酶的其他变体能够抑制端粒酶，同时促进癌症。我们建议编辑端粒酶基因，其方式是通过排除其他剪接来增加端粒延长的效率。增强端粒酶活性的这种机制将使端粒酶表达保持在安全水平，并将排除更高的致癌风险。据推测，编辑神经脑干细胞中的端粒酶基因可以提高成年大脑的神经发生效力，并减缓神经活动的变化。进一步的研究可以导致基因治疗的潜在发展，它可以减缓大脑的衰老过程。