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Multi-omic rejuvenation and lifespan extension upon exposure to youthful circulation

Bohan Zhang, David E. Lee, Alexandre Trapp, Alexander Tyshkovskiy, View ORCID ProfileAke T. Lu, Akshay Bareja, Csaba Kerepesi, Lauren H. Katz, Anastasia V. Shindyapina, View ORCID ProfileSergey E. Dmitriev, Gurpreet S. Baht, View ORCID ProfileSteve Horvath, Vadim N. Gladyshev, James P. White
doi: https://doi.org/10.1101/2021.11.11.468258
Bohan Zhang
1Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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David E. Lee
2Department of Medicine, Duke University School of Medicine, Durham, NC 27701, USA
3Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA
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Alexandre Trapp
1Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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Alexander Tyshkovskiy
1Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
4Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119234, Russia
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Ake T. Lu
5Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA
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  • ORCID record for Ake T. Lu
Akshay Bareja
2Department of Medicine, Duke University School of Medicine, Durham, NC 27701, USA
3Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA
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Csaba Kerepesi
1Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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Lauren H. Katz
3Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA
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Anastasia V. Shindyapina
1Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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Sergey E. Dmitriev
4Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119234, Russia
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  • ORCID record for Sergey E. Dmitriev
Gurpreet S. Baht
2Department of Medicine, Duke University School of Medicine, Durham, NC 27701, USA
3Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA
6Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, 27701, USA
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Steve Horvath
5Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA
7Department of Biostatistics, School of Public Health, University of California, Los Angeles, Los Angeles, CA, 90095, USA
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Vadim N. Gladyshev
1Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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  • For correspondence: vgladyshev@rics.bwh.harvard.edu james.white@duke.edu
James P. White
2Department of Medicine, Duke University School of Medicine, Durham, NC 27701, USA
3Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA
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  • For correspondence: vgladyshev@rics.bwh.harvard.edu james.white@duke.edu
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SUMMARY

Heterochronic parabiosis (HPB) is known for its functional rejuvenation effects across several mouse tissues. However, its impact on the biological age of organisms and their long-term health remains unknown. Here, we performed extended (3-month) HPB, followed by a 2-month detachment period of anastomosed pairs. Old detached mice exhibited improved physiological parameters and lived longer than control isochronic mice. HPB drastically reduced the biological age of blood and liver based on epigenetic analyses across several clock models on two independent platforms; remarkably, this rejuvenation effect persisted even after 2 months of detachment. Transcriptomic and epigenomic profiles of anastomosed mice showed an intermediate phenotype between old and young, suggesting a comprehensive multi-omic rejuvenation effect. In addition, old HPB mice showed transcriptome changes opposite to aging, but akin to several lifespan-extending interventions. Altogether, we reveal that long-term HPB can decrease the biological age of mice, in part through long-lasting epigenetic and transcriptome remodeling, culminating in the extension of lifespan and healthspan.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
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Posted November 12, 2021.
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Multi-omic rejuvenation and lifespan extension upon exposure to youthful circulation
Bohan Zhang, David E. Lee, Alexandre Trapp, Alexander Tyshkovskiy, Ake T. Lu, Akshay Bareja, Csaba Kerepesi, Lauren H. Katz, Anastasia V. Shindyapina, Sergey E. Dmitriev, Gurpreet S. Baht, Steve Horvath, Vadim N. Gladyshev, James P. White
bioRxiv 2021.11.11.468258; doi: https://doi.org/10.1101/2021.11.11.468258
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Multi-omic rejuvenation and lifespan extension upon exposure to youthful circulation
Bohan Zhang, David E. Lee, Alexandre Trapp, Alexander Tyshkovskiy, Ake T. Lu, Akshay Bareja, Csaba Kerepesi, Lauren H. Katz, Anastasia V. Shindyapina, Sergey E. Dmitriev, Gurpreet S. Baht, Steve Horvath, Vadim N. Gladyshev, James P. White
bioRxiv 2021.11.11.468258; doi: https://doi.org/10.1101/2021.11.11.468258

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