Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging
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Abstract
Unlike aged somatic cells, which exhibit a decline in molecular fidelity and eventually reach a state of replicative senescence, pluripotent stem cells can indefinitely replenish themselves while retaining full homeostatic capacity. The conferment of beneficial-pluripotency related traits via in vivo partial cellular reprogramming in vivo partial reprogramming significantly extends lifespan and restores aging phenotypes in mouse models. Although the phases of cellular reprogramming are well characterized, details of the rejuvenation processes are poorly defined. To understand whether cellular reprogramming can ameliorate DNA damage, we created a reprogrammable accelerated aging mouse model with an ERCC1 mutation. Importantly, using enhanced partial reprogramming by combining small molecules with the Yamanaka factors, we observed potent reversion of DNA damage, significant upregulation of multiple DNA damage repair processes, and restoration of the epigenetic clock. In addition, we present evidence that pharmacological inhibition of ALK5 and ALK2 receptors in the TGFb pathway are able to phenocopy some benefits including epigenetic clock restoration suggesting a role in the mechanism of rejuvenation by partial reprogramming.
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Liu, X., Khan, A., Li, H., Wang, S., Chen, X., & Huang, H. (2021) · Current Stem Cell Research & Therapy · doi:10.2174/1574888x16666210714152730 · Cited by 23 · see citing works
Cellular reprogramming and the rise of rejuvenation biotech
de Magalhães, J. P., & Ocampo, A. (2022) · Trends in biotechnology · doi:10.1016/j.tibtech.2022.01.011 · Cited by 23 · see citing works
Self-citationRad51 Regulates Reprogramming Efficiency through DNA Repair Pathway
Lee, J. Y., Kim, D., Ko, J., Kim, K. P., & Park, K. (2016) · Development & Reproduction · doi:10.12717/dr.2016.20.2.163 · Cited by 13 · see citing works
Kuno, A., Nishimura, K., & Takahashi, S. (2018) · BMC Genomics · doi:10.1186/s12864-017-4389-8 · Cited by 12 · see citing works
Flagged first, then by citations
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Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan
(2025) · doi:10.1038/s44321-025-00265-9 · Cited by 49 · see citing works
Self-citationTargeting DNA damage in ageing: towards supercharging DNA repair
Bujarrabal-Dueso, A., Garinis, G. A., Robbins, P. D., Vijg, J., & Schumacher, B. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01212-6 · Cited by 30 · see citing works
Cognitive rejuvenation in old rats by hippocampal OSKM gene therapy
Horvath, S., Lacunza, E., Canatelli-Mallat, M., Portiansky, E. L., Gallardo, M. D., Brooke, R. T., Chiavellini, P., Pasquini, D. C., Girard, M., Lehmann, M., et al. (2024) · GeroScience · doi:10.1007/s11357-024-01269-y · Cited by 14 · see citing works
Self-citationAvelar, R. A., Palmer, D. H., Kulaga, A. Y., & Fuellen, G. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102737 · Cited by 8 · see citing works
Nakatsukasa, Y., Yamada, Y., & Yamada, Y. (2024) · Regenerative Therapy · doi:10.1016/j.reth.2024.11.008 · Cited by 7 · see citing works
A Youthful Touch: Reversal of Aging Hallmarks by Cell Reprogramming
Miliotou, E., & de Lázaro, I. (2024) · Cells Tissues Organs · doi:10.1159/000539415 · Cited by 4 · see citing works
Can iPSCs Turn Back Time? Prospects and Pitfalls in Age Reversal
Ahmad, U., Kumar, D., & Faiyazuddin, M. (2025) · Current Stem Cell Research & Therapy · doi:10.2174/011574888x400606250721112037 · Cited by 2 · see citing works
Promises of reprogramming-induced rejuvenation
Simpson, D. J., Arif, N., Suwanlikit, Y., Kirschner, K., & Chandra, T. (2026) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2026.102484 · Cited by 2 · see citing works
Programmable Lipid Nanoparticle Targeting via Corona EngineeringPreprint
Kayabölen, A., Schmitt-Ulms, C., Elsener, A., Ferraresso, F., Donnelly, K. A., Nan, A. X., Harris, I., Sgrizzi, S. R., Anwer, A., Balestra, I., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.27.708523 · Cited by 1 · see citing works
Self-citationInhibition of mesenchymal drift as a strategy for rejuvenation
Camillo, L. P. D. L. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1715559
Translational Changes upon Aging and Dietary Restriction in Progeroid DNA-Repair-Deficient Mice
Vermeij, W. P., van Galen, I., Ozinga, R. A., Hofman, D. A., van Dinter, J. T., Engels, S. A. G., Smit, K., van Heesch, S., & Hoeijmakers, J. H. J. (2026) · Aging Biology · doi:10.59368/agingbio.20260043
Therapeutic targeting of DNA repair pathway dysregulation in aging, cancer, and neurodegeneration
Kumar, V., Kashif, M., Singh, V., Rawat, R. S., Khan, A., Sarkar, G. C., & Majood, M. (2026) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2026.2683686
Kelm, R. C. (2026) · Journal of Cosmetic Dermatology · doi:10.1111/jocd.71076
- Authors
- Paine, P. T., Rechsteiner, C., Morandini, F., Desdín-Micó, G., Mrabti, C., Parras, A., Haghani, A., Brooke, R., Horvath, S., Seluanov, A., Gorbunova, V., & Ocampo, A.
- Affiliations
- Harvard University (US)
- University of Rochester (US)
- University of Lausanne (CH)
- Altos Labs (US)
- University of California, Los Angeles (US)
- University of Rochester Medicine (US)
- Corresponding author
- Ocampo, Alejandro
- ORCID
- Venue
- Frontiers in Aging
- Publisher
- Frontiers Media SA
- Published
- 2024-01-23
- Volume
- 4
- Pages
- 1323194-1323194
- ISSN
- 2673-6217 (ISSN-L)
- PMC
- PMC10844398
- OpenAlex
- W4391138234
- Cited by
- 13
- References
- 89
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 3
- FWCI
- 1.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Aging (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- IRIS (submittedVersion, cc-by)
- Funders
- National Science Foundation
- Milky Way Research Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (186969)
- Université de Lausanne
- National Institute on Aging (R01AG046320, R01AG027237, P01AG047200, R37AG046320, P01AG051449)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- cellular reprogramming, partial reprogramming, premature aging, DNA repair, Yamanaka factors, small molecules, epigenetic clocks, ALK5 inhibition, TGF-beta signaling, rejuvenation, replicative senescence, lifespan extension
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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