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Reversing age: dual species measurement of epigenetic age with a single clock

View ORCID ProfileSteve Horvath, Kavita Singh, Ken Raj, Shraddha Khairnar, Akshay Sanghavi, Agnivesh Shrivastava, Joseph A. Zoller, Caesar Z. Li, Claudia B. Herenu, Martina Canatelli-Mallat, Marianne Lehmann, Leah C. Solberg Woods, Angel Garcia Martinez, Tengfei Wang, Priscila Chiavellini, Andrew J. Levine, Hao Chen, Rodolfo G. Goya, Harold L. Katcher
doi: https://doi.org/10.1101/2020.05.07.082917
Steve Horvath
1Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
2Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, California, USA
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  • For correspondence: shorvath@mednet.ucla.edu harold@nugenicsresearch.com
Kavita Singh
3Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’S NMIMS University, Mumbai, India
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Ken Raj
4Radiation Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, Didcot, UK
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Shraddha Khairnar
3Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’S NMIMS University, Mumbai, India
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Akshay Sanghavi
5Nugenics Research Pvt Ltd, India
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Agnivesh Shrivastava
5Nugenics Research Pvt Ltd, India
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Joseph A. Zoller
2Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, California, USA
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Caesar Z. Li
2Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, California, USA
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Claudia B. Herenu
6Institute for Experimental Pharmacology of Cordoba (IFEC), School of Chemical Sciences, National University of Cordoba, Cordoba, Argentina
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Martina Canatelli-Mallat
7Biochemistry Research Institute of La Plata – Histology B, Pathology B, School of Medicine, University of La Plata, La Plata CC 455 (zip 1900), Argentina
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Marianne Lehmann
7Biochemistry Research Institute of La Plata – Histology B, Pathology B, School of Medicine, University of La Plata, La Plata CC 455 (zip 1900), Argentina
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Leah C. Solberg Woods
8Wake Forest University School of Medicine, 1 Medical Center Drive, Winston Salem, NC 27157, USA
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Angel Garcia Martinez
9Department of Pharmacology, Addiction Science and Toxicology, The University of Tennessee Health Science Center, Memphis, TN 3993, USA
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Tengfei Wang
9Department of Pharmacology, Addiction Science and Toxicology, The University of Tennessee Health Science Center, Memphis, TN 3993, USA
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Priscila Chiavellini
7Biochemistry Research Institute of La Plata – Histology B, Pathology B, School of Medicine, University of La Plata, La Plata CC 455 (zip 1900), Argentina
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Andrew J. Levine
10Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, CA, 90095, USA
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Hao Chen
9Department of Pharmacology, Addiction Science and Toxicology, The University of Tennessee Health Science Center, Memphis, TN 3993, USA
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Rodolfo G. Goya
7Biochemistry Research Institute of La Plata – Histology B, Pathology B, School of Medicine, University of La Plata, La Plata CC 455 (zip 1900), Argentina
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Harold L. Katcher
5Nugenics Research Pvt Ltd, India
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  • For correspondence: shorvath@mednet.ucla.edu harold@nugenicsresearch.com
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Abstract

Young blood plasma is known to confer beneficial effects on various organs in mice. However, it was not known whether young plasma rejuvenates cells and tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly-accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=593 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=850 human tissue samples to the training data. We employed these six clocks to investigate the rejuvenation effects of a plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs. Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging.

Competing Interest Statement

Several authors are founders, owners, employees (Harold Katcher and Akshay Sanghavi) or consultants of Nugenics Research (Steve Horvath and Agnivesh Shrivastava) which plans to commercialize the "Elixir" treatment. Other authors (Kavita Singh, Shraddha Khairnar) received financial support from Nugenics Research. The other authors do not have conflict of interest.

Footnotes

  • ↵# Joint first authorship

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Reversing age: dual species measurement of epigenetic age with a single clock
Steve Horvath, Kavita Singh, Ken Raj, Shraddha Khairnar, Akshay Sanghavi, Agnivesh Shrivastava, Joseph A. Zoller, Caesar Z. Li, Claudia B. Herenu, Martina Canatelli-Mallat, Marianne Lehmann, Leah C. Solberg Woods, Angel Garcia Martinez, Tengfei Wang, Priscila Chiavellini, Andrew J. Levine, Hao Chen, Rodolfo G. Goya, Harold L. Katcher
bioRxiv 2020.05.07.082917; doi: https://doi.org/10.1101/2020.05.07.082917
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Reversing age: dual species measurement of epigenetic age with a single clock
Steve Horvath, Kavita Singh, Ken Raj, Shraddha Khairnar, Akshay Sanghavi, Agnivesh Shrivastava, Joseph A. Zoller, Caesar Z. Li, Claudia B. Herenu, Martina Canatelli-Mallat, Marianne Lehmann, Leah C. Solberg Woods, Angel Garcia Martinez, Tengfei Wang, Priscila Chiavellini, Andrew J. Levine, Hao Chen, Rodolfo G. Goya, Harold L. Katcher
bioRxiv 2020.05.07.082917; doi: https://doi.org/10.1101/2020.05.07.082917

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