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Abstract

Aging is characterized by the progressive loss of cellular function, the accumulation of epigenetic and transcriptional changes, and a decline in tissue homeostasis. Induced pluripotent stem cells (iPSCs), derived from somatic cells through expression of Yamanaka factors (OCT4, SOX2, KLF4, MYC; OSKM), undergo epigenetic rejuvenation, effectively resetting their biological age. Partial reprogramming, characterized by the transient or cyclic expression of reprogramming factors, has emerged as a promising method to reverse aging hallmarks without erasing cellular identity. This study aims to synthesize findings from studies on iPSC-based age reversal, covering mechanisms, therapeutic potential, challenges, and translational hurdles. While partial reprogramming can restore youthful gene expression, DNA methylation patterns, and mitochondrial function, and reduce senescence markers, major safety concerns remain, including genomic instability, tumorigenesis, and incomplete control over identity retention. The field is rapidly progressing, yet fundamental questions about long-term safety, efficacy, and optimal protocols must be resolved before clinical translation.

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2025-07-28
2025-10-03

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References

  1. Ocampo A. Reddy P. Martinez-Redondo P. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell 2016 167 7 1719 1733.e12 10.1016/j.cell.2016.11.052 27984723
    [Google Scholar]
  2. Olova N. Simpson D.J. Marioni R.E. Chandra T. Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity. Aging Cell 2019 18 1 e12877 10.1111/acel.12877 30450724
    [Google Scholar]
  3. Yang J.H. Petty C.A. Dixon-McDougall T. Chemically induced reprogramming to reverse cellular aging. Aging (Albany NY) 2023 15 13 5966 5989 10.18632/aging.204896 37437248
    [Google Scholar]
  4. Mendelsohn A.R. Larrick J.W. Lei J.L. Rejuvenation by partial reprogramming of the epigenome. Rejuvenation Res. 2017 20 2 146 150 10.1089/rej.2017.1958 28314379
    [Google Scholar]
  5. Puri D. Wagner W. Epigenetic rejuvenation by partial reprogramming. BioEssays 2023 45 4 2200208 10.1002/bies.202200208 36871150
    [Google Scholar]
  6. Gill D. Parry A. Santos F. Multi-omic rejuvenation of human cells by maturation phase transient reprogramming. eLife 2022 11 e71624 10.7554/eLife.71624 35390271
    [Google Scholar]
  7. Mendelsohn A.R. Mendelsohn A.R. Lei J. Rejuvenation through iPSCs and reprogramming in vivo and in vitro. In: Current Topics in iPSCs Technology. Elsevier 2022 571 587 10.1016/B978‑0‑323‑99892‑5.00015‑3
    [Google Scholar]
  8. Esteves F. Brito D. Rajado A.T. Reprogramming iPSCs to study age-related diseases: Models, therapeutics, and clinical trials. Mech. Ageing Dev. 2023 214 111854 10.1016/j.mad.2023.111854 37579530
    [Google Scholar]
  9. Mitchell W. Goeminne L.J.E. Tyshkovskiy A. Multi-omics characterization of partial chemical reprogramming reveals evidence of cell rejuvenation. eLife 2024 12 RP90579 10.7554/eLife.90579.3 38517750
    [Google Scholar]
  10. Singh P.B. Zhakupova A. Age reprogramming: Cell rejuvenation by partial reprogramming. Development 2022 149 22 dev200755 10.1242/dev.200755 36383700
    [Google Scholar]
  11. Paakinaho V. Lempiäinen J.K. Sigismondo G. SUMOylation regulates the protein network and chromatin accessibility at glucocorticoid receptor-binding sites. Nucleic Acids Res. 2021 49 4 1951 1971 10.1093/nar/gkab032 33524141
    [Google Scholar]
  12. Zhu Q. Liang P. Chu C. Zhang A. Zhou W. Protein sumoylation in normal and cancer stem cells. Front. Mol. Biosci. 2022 9 1095142 10.3389/fmolb.2022.1095142 36601585
    [Google Scholar]
  13. Sahu SK Reddy P Lu J Targeted partial reprogramming of age-associated cell states improves markers of health in mouse models of aging. Sci Transl Med 2024 16 764 eadg1777 10.1126/scitranslmed.adg1777 39259812
    [Google Scholar]
  14. Macip C.C. Hasan R. Hoznek V. Gene Therapy-mediated partial reprogramming extends lifespan and reverses age-related changes in aged mice. Cell. Reprogram. 2024 26 1 24 32 10.1089/cell.2023.0072 38381405
    [Google Scholar]
  15. Xu L Ramirez-Matias J Hauptschein M Partial reprogramming of the aging neurogenic niche. Innov Aging 2024 8 268 9 (Suppl. 1) 10.1093/geroni/igae098.0870
    [Google Scholar]
  16. Mishra A. Modi U. Sharma R. Bhatia D. Solanki R. Biochemical and biophysical cues of the extracellular matrix modulates stem cell fate: Progress and prospect in extracellular matrix mimicking biomaterials. Biomed Eng Adv 2025 9 100143 10.1016/j.bea.2024.100143
    [Google Scholar]
  17. Akhavan O. Ghaderi E. Abouei E. Hatamie S. Ghasemi E. Accelerated differentiation of neural stem cells into neurons on ginseng-reduced graphene oxide sheets. Carbon 2014 66 395 406 10.1016/j.carbon.2013.09.015
    [Google Scholar]
  18. Akhavan O. Ghaderi E. Differentiation of human neural stem cells into neural networks on graphene nanogrids. J. Mater. Chem. B Mater. Biol. Med. 2013 1 45 6291 6301 10.1039/c3tb21085e 32261702
    [Google Scholar]
  19. Saadati M. Akhavan O. Fazli H. Nemati S. Baharvand H. Controlled differentiation of human neural progenitor cells on molybdenum disulfide/graphene oxide heterojunction scaffolds by photostimulation. ACS Appl. Mater. Interfaces 2023 15 3 3713 3730 10.1021/acsami.2c15431 36633466
    [Google Scholar]
  20. Akhavan O. Ghaderi E. Shirazian S.A. Near infrared laser stimulation of human neural stem cells into neurons on graphene nanomesh semiconductors. Colloids Surf. B Biointerfaces 2015 126 313 321 10.1016/j.colsurfb.2014.12.027 25578421
    [Google Scholar]
  21. Akhavan O. Ghaderi E. The use of graphene in the self-organized differentiation of human neural stem cells into neurons under pulsed laser stimulation. J. Mater. Chem. B Mater. Biol. Med. 2014 2 34 5602 5611 10.1039/C4TB00668B 32262194
    [Google Scholar]
  22. Akhavan O. Ghaderi E. Shirazian S.A. Rahighi R. Rolled graphene oxide foams as three-dimensional scaffolds for growth of neural fibers using electrical stimulation of stem cells. Carbon 2016 97 71 77 10.1016/j.carbon.2015.06.079
    [Google Scholar]
  23. Akhavan O. Graphene scaffolds in progressive nanotechnology/stem cell-based tissue engineering of the nervous system. J. Mater. Chem. B Mater. Biol. Med. 2016 4 19 3169 3190 10.1039/C6TB00152A 32263253
    [Google Scholar]
  24. Zhang T. Ke W. Zhou X. Human neural stem cells reinforce hippocampal synaptic network and rescue cognitive deficits in a mouse model of alzheimer’s disease. Stem Cell Reports 2019 13 6 1022 1037 10.1016/j.stemcr.2019.10.012 31761676
    [Google Scholar]
  25. Haubenreich C. Lenz M. Schuppert A. Epigenetic and transcriptional shifts in human neural stem cells after reprogramming into induced pluripotent stem cells and subsequent redifferentiation. Int. J. Mol. Sci. 2024 25 6 3214 10.3390/ijms25063214 38542188
    [Google Scholar]
  26. Lee S.Y. George J.H. Nagel D.A. Ye H. Kueberuwa G. Seymour L.W. Optogenetic control of iPS cell‐derived neurons in 2D and 3D culture systems using channelrhodopsin‐2 expression driven by the synapsin‐1 and calcium‐calmodulin kinase II promoters. J. Tissue Eng. Regen. Med. 2019 13 3 369 384 10.1002/term.2786 30550638
    [Google Scholar]
  27. Chondronasiou D. Gill D. Mosteiro L. Multi‐omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming. Aging Cell 2022 21 3 e13578 10.1111/acel.13578 35235716
    [Google Scholar]
  28. Paine P.T. Rechsteiner C. Morandini F. Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging. Front Aging 2024 4 1323194 10.3389/fragi.2023.1323194 38322248
    [Google Scholar]
  29. Kaur P. Otgonbaatar A. Ramamoorthy A. Combining stem cell rejuvenation and senescence targeting to synergistically extend lifespan. Aging (Albany NY) 2022 14 20 8270 8291 10.18632/aging.204347 36287172
    [Google Scholar]
  30. Li X. Zhang H. Wang X. iPSC-derived exosomes promote angiogenesis in naturally aged mice. Aging (Albany NY) 2023 15 12 5854 5872 10.18632/aging.204845 37367945
    [Google Scholar]
  31. Milhavet O. Lemaitre J.M. Senescent-derived pluripotent stem cells are able to redifferentiate into fully rejuvenated cells. In: Tumor Dormancy, Quiescence, and Senescence. Dordrecht Springer Netherlands 2014 265 276 10.1007/978‑94‑007‑7726‑2_25
    [Google Scholar]
  32. Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013 14 10 3156 10.1186/gb‑2013‑14‑10‑r115 24138928
    [Google Scholar]
  33. Levine M.E. Lu A.T. Quach A. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY) 2018 10 4 573 591 10.18632/aging.101414 29676998
    [Google Scholar]
  34. Marzec-Schmidt K. Ghosheh N. Stahlschmidt S.R. Küppers-Munther B. Synnergren J. Ulfenborg B. Artificial intelligence supports automated characterization of differentiated human pluripotent stem cells. Stem Cells 2023 41 9 850 861 10.1093/stmcls/sxad049 37357747
    [Google Scholar]
  35. Vo Q.D. Saito Y. Ida T. Nakamura K. Yuasa S. The use of artificial intelligence in induced pluripotent stem cell-based technology over 10-year period: A systematic scoping review. PLoS One 2024 19 5 e0302537 10.1371/journal.pone.0302537 38771829
    [Google Scholar]
  36. Ramakrishna R.R. Abd Hamid Z. Wan Zaki W.M.D. Huddin A.B. Mathialagan R. Stem cell imaging through convolutional neural networks: current issues and future directions in artificial intelligence technology. PeerJ 2020 8 e10346 10.7717/peerj.10346 33240655
    [Google Scholar]
  37. Sniecinski I. Seghatchian J. Artificial intelligence: A joint narrative on potential use in pediatric stem and immune cell therapies and regenerative medicine. Transfus. Apheresis Sci. 2018 57 3 422 424 10.1016/j.transci.2018.05.004 29784537
    [Google Scholar]
  38. Shahwar Anwar S. Ahmad U. Muazzam Khan M. Artificial Intelligence in Healthcare: An Overview. In: Smart Drug Delivery. IntechOpen 2022
    [Google Scholar]
  39. Miliotou E. de Lázaro I. A youthful touch: Reversal of aging hallmarks by cell reprogramming. Cells Tissues Organs 2024 213 6 1 13 10.1159/000539415 38768583
    [Google Scholar]
  40. pH-sensitive chitosan hydrogel with instant gelation for myocardial regeneration. J. Tissue Sci. Eng. 2017 08 03
    [Google Scholar]
  41. Yadalam P.K. Munivel S. Ardila C.M. AI revolutionizes cellular reprogramming of periodontal ligament. Int. Dent. J. 2024 74 6 1464 1465 10.1016/j.identj.2024.08.009 39227238
    [Google Scholar]
  42. Prosz A. Pipek O. Börcsök J. Biologically informed deep learning for explainable epigenetic clocks. Sci. Rep. 2024 14 1 1306 10.1038/s41598‑023‑50495‑5 38225268
    [Google Scholar]
  43. Hashemi E. Akhavan O. Shamsara M. Graphene oxide negatively regulates cell cycle in embryonic fibroblast cells. Int. J. Nanomedicine 2020 15 6201 6209 10.2147/IJN.S260228 32884270
    [Google Scholar]
  44. Jalilinejad N. Rabiee M. Baheiraei N. Electrically conductive carbon‐based (bio)‐nanomaterials for cardiac tissue engineering. Bioeng. Transl. Med. 2023 8 1 e10347 10.1002/btm2.10347 36684103
    [Google Scholar]
  45. Hicks M.R. Saleh K.K. Clock B. Regenerating human skeletal muscle forms an emerging niche in vivo to support PAX7 cells. Nat. Cell Biol. 2023 25 12 1758 1773 10.1038/s41556‑023‑01271‑0 37919520
    [Google Scholar]
  46. Maghsoudi S. Taghavi Shahraki B. Rameh F. A review on computer‐aided chemogenomics and drug repositioning for rational COVID ‐19 drug discovery. Chem. Biol. Drug Des. 2022 100 5 699 721 10.1111/cbdd.14136 36002440
    [Google Scholar]
  47. Rahimnejad M. Nasrollahi Boroujeni N. Jahangiri S. Prevascularized micro-/nano-sized spheroid/bead aggregates for vascular tissue engineering. Nano-Micro Lett. 2021 13 1 182 10.1007/s40820‑021‑00697‑1 34409511
    [Google Scholar]
  48. Akhavan O. Ghaderi E. Flash photo stimulation of human neural stem cells on graphene/TiO2 heterojunction for differentiation into neurons. Nanoscale 2013 5 21 10316 10326 10.1039/c3nr02161k 24056702
    [Google Scholar]
  49. Migliorini A. Ge S. Atkins M.H. Embryonic macrophages support endocrine commitment during human pancreatic differentiation. Cell Stem Cell 2024 31 11 1591 1611.e8 10.1016/j.stem.2024.09.011 39406230
    [Google Scholar]
  50. Lehmann M. Canatelli-Mallat M. Chiavellini P. Cónsole G.M. Gallardo M.D. Goya R.G. Partial reprogramming as an emerging strategy for safe induced cell generation and rejuvenation. Curr. Gene Ther. 2019 19 4 248 254 10.2174/1566523219666190902154511 31475896
    [Google Scholar]
  51. Chen R. Skutella T. Synergistic anti-ageing through senescent cells specific reprogramming. Cells 2022 11 5 830 10.3390/cells11050830 35269453
    [Google Scholar]
  52. Shorokhova M.A. Partial cell reprogramming as a way to revitalize living systems. Cell Tissue Biol. 2024 18 2 103 114 10.1134/S1990519X23700104
    [Google Scholar]
/content/journals/cscr/10.2174/011574888X400606250721112037
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Can iPSCs Turn Back Time? Prospects and Pitfalls in Age Reversal
Bentham Science Publishers ; https://doi.org/10.2174/011574888X400606250721112037
/content/journals/cscr/10.2174/011574888X400606250721112037
/content/journals/cscr/10.2174/011574888X400606250721112037
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  • Article Type:     Review Article
Keywords: metabolic dysfunctions ; partial reprogramming ; aging reversal ; Induced pluripotent stem cells (iPSCs) ; epigenetic rejuvenation ; cellular reprogramming safety

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