Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging
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 viv...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Aging |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fragi.2023.1323194/full |
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| author | Patrick Treat Paine Patrick Treat Paine Cheyenne Rechsteiner Francesco Morandini Gabriela Desdín-Micó Calida Mrabti Alberto Parras Alberto Parras Amin Haghani Robert Brooke Steve Horvath Steve Horvath Steve Horvath Andrei Seluanov Andrei Seluanov Vera Gorbunova Vera Gorbunova Alejandro Ocampo Alejandro Ocampo |
| author_facet | Patrick Treat Paine Patrick Treat Paine Cheyenne Rechsteiner Francesco Morandini Gabriela Desdín-Micó Calida Mrabti Alberto Parras Alberto Parras Amin Haghani Robert Brooke Steve Horvath Steve Horvath Steve Horvath Andrei Seluanov Andrei Seluanov Vera Gorbunova Vera Gorbunova Alejandro Ocampo Alejandro Ocampo |
| author_sort | Patrick Treat Paine |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T12:07:32Z |
| format | Article |
| id | doaj.art-3cf34d95781547ddadab3e678f935ae3 |
| institution | Directory Open Access Journal |
| issn | 2673-6217 |
| language | English |
| last_indexed | 2024-03-08T12:07:32Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging |
| spelling | doaj.art-3cf34d95781547ddadab3e678f935ae32024-01-23T04:24:48ZengFrontiers Media S.A.Frontiers in Aging2673-62172024-01-01410.3389/fragi.2023.13231941323194Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature agingPatrick Treat Paine0Patrick Treat Paine1Cheyenne Rechsteiner2Francesco Morandini3Gabriela Desdín-Micó4Calida Mrabti5Alberto Parras6Alberto Parras7Amin Haghani8Robert Brooke9Steve Horvath10Steve Horvath11Steve Horvath12Andrei Seluanov13Andrei Seluanov14Vera Gorbunova15Vera Gorbunova16Alejandro Ocampo17Alejandro Ocampo18Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Lausanne, SwitzerlandCenter for Virology and Vaccine Research, Harvard Medical School, Boston, MA, United StatesDepartment of Biology, University of Rochester, Rochester, NY, United StatesDepartment of Biology, University of Rochester, Rochester, NY, United StatesDepartment of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Lausanne, SwitzerlandDepartment of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Lausanne, SwitzerlandDepartment of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Lausanne, SwitzerlandEPITERNA SA, Vaud, SwitzerlandAltos Labs, San Diego, CA, United StatesEpigenetic Clock Development Foundation, Torrance, CA, United StatesAltos Labs, San Diego, CA, United StatesEpigenetic Clock Development Foundation, Torrance, CA, United StatesHuman Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United StatesDepartment of Biology, University of Rochester, Rochester, NY, United StatesDepartment of Medicine, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Biology, University of Rochester, Rochester, NY, United StatesDepartment of Medicine, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Lausanne, SwitzerlandEPITERNA SA, Vaud, SwitzerlandUnlike 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.https://www.frontiersin.org/articles/10.3389/fragi.2023.1323194/fullagingDNA damageercc1cellular reprogrammingTGFb |
| spellingShingle | Patrick Treat Paine Patrick Treat Paine Cheyenne Rechsteiner Francesco Morandini Gabriela Desdín-Micó Calida Mrabti Alberto Parras Alberto Parras Amin Haghani Robert Brooke Steve Horvath Steve Horvath Steve Horvath Andrei Seluanov Andrei Seluanov Vera Gorbunova Vera Gorbunova Alejandro Ocampo Alejandro Ocampo Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging Frontiers in Aging aging DNA damage ercc1 cellular reprogramming TGFb |
| title | Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging |
| title_full | Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging |
| title_fullStr | Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging |
| title_full_unstemmed | Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging |
| title_short | Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging |
| title_sort | initiation phase cellular reprogramming ameliorates dna damage in the ercc1 mouse model of premature aging |
| topic | aging DNA damage ercc1 cellular reprogramming TGFb |
| url | https://www.frontiersin.org/articles/10.3389/fragi.2023.1323194/full |
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