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PreprintCited by 13Pluripotent Stem Cells ResearchTelomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model Organisms

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Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging

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Paine, Patrick Treat, Rechsteiner, Cheyenne, Morandini, Francesco, Desdin Mico, Gabriela, Mrabti, Calida, Parras, Alberto, Haghani, Amin, Brooke, Robert, Horvath, Steve, Seluanov, Andrei, Gorbunova, Vera, Ocampo, Alejandro·2023·Frontiers in Aging
DOI 10.1101/2023.05.12.540500PMC PMC10844398

Preprint — published as 10.3389/fragi.2023.1323194 · Paper page

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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 (IVPR) 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 epigenetic reprogramming can ameliorate DNA damage, we created 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 TGFb pathway is able to phenocopy some benefits including epigenetic clock restoration suggesting a role in the mechanism of rejuvenation by partial reprogramming.

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Metadata

Authors
Paine, P. T., Rechsteiner, C., Morandini, F., Desdin Mico, 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
openRxiv
Published
2023-05-14
Volume
4
Pages
1323194-1323194
ISSN
2673-6217 (ISSN-L)
DOI
10.1101/2023.05.12.540500
PMC
PMC10844398
OpenAlex
W4391138234
Cited by
13
References
1
Citations by year
2026: 5 · 2025: 5 · 2024: 3
FWCI
1.77
Type
journal article
Language
en
Open access
Licence
cc-by
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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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

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