Priority Research Paper Volume 15, Issue 13 pp 5966—5989

Chemically induced reprogramming to reverse cellular aging

Jae-Hyun Yang1, *, , Christopher A. Petty1, *, , Thomas Dixon-McDougall1, *, , Maria Vina Lopez4, , Alexander Tyshkovskiy2,3, , Sun Maybury-Lewis1, , Xiao Tian1, , Nabilah Ibrahim1, , Zhili Chen1, , Patrick T. Griffin1, , Matthew Arnold1, , Jien Li1, , Oswaldo A. Martinez1,5, , Alexander Behn1, , Ryan Rogers-Hammond1, , Suzanne Angeli4, , Vadim N. Gladyshev2, , David A. Sinclair1, ,

  • 1 Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA 02115, USA
  • 2 Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
  • 3 Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119234, Russia
  • 4 Molecular and Biomedical Sciences, University of Maine, Orono, ME 04467, USA
  • 5 Department of Biology and Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
* Equal contribution

Received: June 30, 2023       Accepted: July 4, 2023       Published: July 12, 2023
How to Cite

Copyright: © 2023 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


A hallmark of eukaryotic aging is a loss of epigenetic information, a process that can be reversed. We have previously shown that the ectopic induction of the Yamanaka factors OCT4, SOX2, and KLF4 (OSK) in mammals can restore youthful DNA methylation patterns, transcript profiles, and tissue function, without erasing cellular identity, a process that requires active DNA demethylation. To screen for molecules that reverse cellular aging and rejuvenate human cells without altering the genome, we developed high-throughput cell-based assays that distinguish young from old and senescent cells, including transcription-based aging clocks and a real-time nucleocytoplasmic compartmentalization (NCC) assay. We identify six chemical cocktails, which, in less than a week and without compromising cellular identity, restore a youthful genome-wide transcript profile and reverse transcriptomic age. Thus, rejuvenation by age reversal can be achieved, not only by genetic, but also chemical means.


ALS: Amyotrophic lateral sclerosis; β-ME: β-mercaptoethanol; CiPSCs: chemically induced pluripotent stem cells; CCFs: cytoplasmic chromatin fragments; EPOCH: epigenetic programming of old cell health; FTD: frontotemporal dementia; GO: gene ontology; HGPS: Hutchinson-Gilford progeria syndrome; hiPSCs: human induced pluripotent stem cells; iPSCs: induced pluripotent stem cells; ICE: inducible changes in the epigenome; IF: immunofluorescence; NES: nuclear export signal; NLS: nuclear localization signal; NCC: nucleocytoplasmic compartmentalization; OSK: OCT4, SOX2, and KLF4; OSKM: OCT4, SOX2, KLF4, and cMYC; PFA: paraformaldehyde; SASP: senescence associated secretory phenotype; SKM: SOX2, KLF4, and cMYC; Tet-on: tetracycline-inducible promoter; tAge: transcriptomic age.