Our understanding of cell aging advanced significantly since the discovery of this phenomenon by Hayflick and Moorhead in 1961. In addition to the well-known shortening of telomeric regions of chromosomes, cell aging is closely associated with changes of the DNA methylation profile. Establishing, maintaining, or reversing epigenetic age of a cell is central to the technology of cell reprogramming. Two distinct approaches - iPSC- and transdifferentiation-based cell reprogramming - affect differently epigenetic age of the cells. The iPSC-based reprogramming protocols are generally believed to result in the reversion of DNA methylation profiles towards less differentiated states, while the original methylation profiles are preserved in the direct trans-differentiation protocols. Clearly, in order to develop adequate model of CNS pathologies, one has to have thorough understanding of the biological roles of DNA methylation in the development, maintenance of functional activity, tissue and cell diversity, restructuring of neural networks during learning, as well as in aging-associated neuronal decline. Direct cell reprogramming is an excellent alternative and a valuable supplement to the iPSC-based technologies both as a source of mature cells for modeling of neurodegenerative diseases, and as a novel powerful strategy for in vivo cell replacement therapy. Further advancement of the regenerative and personalized medicine will strongly depend on optimization of the production of patient-specific autologous cells involving alternative approaches of direct and indirect cell reprogramming that take into account epigenetic age of the starting cell material.

中文翻译：

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细胞重编程保留表观遗传年龄：优点和局限性

自 1961 年 Hayflick 和 Moorhead 发现这一现象以来，我们对细胞衰老的理解有了显着进步。除了众所周知的染色体端粒区域缩短之外，细胞衰老还与 DNA 甲基化谱的变化密切相关。建立、维持或逆转细胞的表观遗传年龄是细胞重编程技术的核心。两种不同的方法 - 基于 iPSC 和转分化的细胞重编程 - 影响细胞的不同表观遗传年龄。通常认为基于 iPSC 的重编程协议会导致 DNA 甲基化图谱向分化程度较低的状态逆转，而原始甲基化图谱在直接转分化协议中得以保留。显然，为了开发适当的 CNS 病理模型，人们必须彻底了解 DNA 甲基化在发育、功能活动维持、组织和细胞多样性、学习过程中神经网络的重组以及与衰老相关的神经元衰退中的生物学作用。直接细胞重编程是基于 iPSC 技术的一种极好的替代方法和有价值的补充，既可以作为用于神经退行性疾病建模的成熟细胞来源，也可以作为体内细胞替代疗法的一种新的强大策略。再生和个性化医疗的进一步发展将在很大程度上取决于患者特异性自体细胞生产的优化，包括考虑到起始细胞材料的表观遗传年龄的直接和间接细胞重编程的替代方法。