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Universal DNA methylation age across mammalian tissues

By Ake T Lu, Zhe Fei, Amin Haghani, Todd R. Robeck, Joseph A Zoller, Caesar Z Li, Joshua Zhang, Julia Ablaeva, Danielle M Adams, Javier Almunia, Reza Ardehali, Adriana Arneson, C. Scott Baker, Katherine Belov, Pete Black, Daniel T Blumstein, Eleanor K. Bors, Charles Breeze, Robert T. Brooke, Janine Brown, Alex Caulton, Julie M. Cavin, Ioulia Chatzistamou, Hao Chen, Priscila Chiavellini, Oi-Wa Choi, Shannon Clarke, Joseph DeYoung, Christopher Dold, Candice K. Emmons, Stephan Emmrich, Chris G. Faulkes, Steven H. Ferguson, Carrie J. Finno, Jean-Michel Gaillard, Eva Garde, Vadim N. Gladyshev, Vera Gorbunova, Rodolfo G Goya, Matthew J Grant, Erin N. Hales, M. Bradley Hanson, Martin Haulena, Andrew N. Hogan, Carolyn J. Hogg, Timothy A Hore, Anna J. Jasinska, Gareth Jones, Eve Jourdain, Olga Kashpur, Harold Katcher, Etsuko Katsumata, Vimala Kaza, Hippokratis Kiaris, Michael S. Kobor, Pawel Kordowitzki, William R. Koski, Brenda Larison, Sang-Goo Lee, Ye C. Lee, Marianne Lehmann, Jean-Francois Lemaitre, Andrew J. Levine, Cun Li, Xinmin Li, David TS Lin, Nicholas Macoretta, Dewey Maddox, Craig O. Matkin, Julie A. Mattison, June Mergl, Jennifer J. Meudt, Khyobeni Mozhui, Asieh Naderi, Martina Nagy, Pritika Narayan, Peter W. Nathanielsz, Ngoc B. Nguyen, Christof Niehrs, Alexander G Ophir, Elaine A. Ostrander, Perrie O'Tierney Ginn, Kim M. Parsons, Kimberly C. Paul, Matteo Pellegrini, Gabriela M. Pinho, Jocelyn Plassais, Natalia A. Prado, Benjamin Rey, Beate R. Ritz, Jooke Robbins, Magdalena Rodriguez, Jennifer Russell, Elena Rydkina, Lindsay L. Sailer, Adam B Salmon, Akshay Sanghavi, Kyle M. Schachtschneider, Dennis Schmitt, Todd Schmitt, Lars Schomacher, Lawrence B Schook, Karen E. Sears, Andrei Seluanov, Dhanansayan Shanmuganayagam, Anastasia Shindyapina, Kavita Singh, Ishani Sinha, Russel G. Snell, Elham Soltanmaohammadi, Matthew L. Spangler, Lydia Staggs, Karen J. Steinman, Victoria J Sugrue, Balazs Szladovits, Masaki Takasugi, Emma C. Teeling, Michael J. Thompson, Bill Van Bonn, Sonja C. Vernes, Diego Villar, Harry V Vinters, Mary C. Wallingford, Nan Wang, Robert K. Wayne, Gerald S. Wilkinson, Christopher K. Williams, Robert W. Williams, X. William Yang, Brent G. Young, Bohan Zhang, Zhihui Zhang, Peng Zhao, Yang Zhao, Joerg Zimmermann, Wanding Zhou, Jason Ernst, Ken Raj, Steve Horvath

Posted 19 Jan 2021
bioRxiv DOI: 10.1101/2021.01.18.426733

Aging is often perceived as a degenerative process caused by random accrual of cellular damage over time. In spite of this, age can be accurately estimated by epigenetic clocks based on DNA methylation profiles from almost any tissue of the body. Since such pan-tissue epigenetic clocks have been successfully developed for several different species, it is difficult to ignore the likelihood that a defined and shared mechanism instead, underlies the aging process. To address this, we generated 10,000 methylation arrays, each profiling up to 37,000 cytosines in highly-conserved stretches of DNA, from over 59 tissue-types derived from 128 mammalian species. From these, we identified and characterized specific cytosines, whose methylation levels change with age across mammalian species. Genes associated with these cytosines are greatly enriched in mammalian developmental processes and implicated in age-associated diseases. From the methylation profiles of these age-related cytosines, we successfully constructed three highly accurate universal mammalian clocks for eutherians, and one universal clock for marsupials. The universal clocks for eutherians are similarly accurate for estimating ages (r>0.96) of any mammalian species and tissue with a single mathematical formula. Collectively, these new observations support the notion that aging is indeed evolutionarily conserved and coupled to developmental processes across all mammalian species - a notion that was long-debated without the benefit of this new and compelling evidence.

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