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Received July 28, 2020; Revised July 28, 2020; Accepted August 5, 2020
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.
KEY WORDS: regenerative medicine, epigenetic clock, direct cell reprogramming, induced pluripotent stem cells, embryonic stem cells, telomeres, methylome