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While this paradigm has been shown to be associated with epigenetic de\u2010aging, the dynamics of this process have remained unclear. Here, we used overexpression of the two reprogramming factors SOX2 and cMYC to generate iNSCs from erythroid progenitors of donors ranging from neonatal to 101\u2009years of age. Using an epigenetic aging clock algorithm, we corroborated our previous finding that iNSCs generated from aged donors show pronounced epigenetic de\u2010aging, preserving around 13% and 5% of the original donor age at low and high passages, respectively. Studying the dynamics of epigenetic de\u2010aging during iNSC conversion across time, we found that this process is largely protracted, continuing for several weeks and even under proliferation\u2010inhibiting conditions. Transcriptomic differences between young and old donor\u2010derived iNSCs dissipate with extended time in conversion, too. Concordant with this observation, established iNSC lines lack age\u2010associated cellular hallmarks, similar to induced pluripotent stem cells and their derivatives. Interestingly, time course analysis of DNA methylation and RNA sequencing data revealed that acquisition of a\n                    <jats:italic>bona fide<\/jats:italic>\n                    NSC signature extends greatly beyond the time point when proliferative PAX6\u2010positive iNSCs emerge. The unexpected slow dynamics of these processes make iNSC conversion an attractive model for dissecting the mechanisms underlying somatic transdifferentiation and epigenetic de\u2010aging.\n                  <\/jats:p>","DOI":"10.1111\/acel.70751","type":"journal-article","created":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T03:40:46Z","timestamp":1791085246000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Protracted Fate Acquisition and Epigenetic De\u2010Aging During Induced Neural Stem Cell Conversion of Human Blood Cells"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2746-6519","authenticated-orcid":false,"given":"Lea Jessica","family":"Berg","sequence":"first","affiliation":[{"name":"Institute of Reconstructive Neurobiology University of Bonn Medical Faculty &amp; University Hospital Bonn  Bonn 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University Hospital Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Sheng","sequence":"additional","affiliation":[{"name":"Institute of Reconstructive Neurobiology University of Bonn Medical Faculty &amp; University Hospital Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Peitz","sequence":"additional","affiliation":[{"name":"Institute of Reconstructive Neurobiology University of Bonn Medical Faculty &amp; University Hospital Bonn  Bonn Germany"},{"name":"Cell Programming Core Facility University of Bonn Medical Faculty &amp; University Hospital Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0139-9143","authenticated-orcid":false,"given":"Andreas","family":"Till","sequence":"additional","affiliation":[{"name":"Institute of Reconstructive Neurobiology University of Bonn Medical Faculty &amp; University Hospital Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1971-3217","authenticated-orcid":false,"given":"Wolfgang","family":"Wagner","sequence":"additional","affiliation":[{"name":"Helmholtz\u2010Institute for Biomedical Engineering RWTH Aachen University Medical School  Aachen Germany"},{"name":"Institute for Stem Cell Biology RWTH Aachen University Medical School  Aachen Germany"},{"name":"Center for Integrated Oncology Aachen Bonn Cologne D\u00fcsseldorf (CIO ABCD)  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1277-0980","authenticated-orcid":false,"given":"Oliver","family":"Br\u00fcstle","sequence":"additional","affiliation":[{"name":"Institute of Reconstructive Neurobiology University of Bonn Medical Faculty &amp; University Hospital Bonn  Bonn Germany"},{"name":"LIFE &amp; BRAIN GmbH  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,3]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu049"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287\u2010024\u201004110\u20107"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3473"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2021.06.003"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.18926.1"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.71624"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw313"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2015.11.019"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb\u20102013\u201014\u201010\u2010r115"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.101508"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3252"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.18648"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr095"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1103113108"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.04.105"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.173922.111.2248"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2021.07.006"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3749"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43587\u2010023\u201000462\u20106"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1387\/ijdb.103186fm"},{"issue":"1","key":"e_1_2_12_24_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.14806\/ej.17.1.200","article-title":"Cutadapt 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