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Epigenetic predictors of maximum lifespan and other life history traits in mammals

By Caesar Z Li, Amin Haghani, Todd R. Robeck, Diego Villar, Ake T Lu, Joshua Zhang, Chris G. Faulkes, Ha Thai Vu, Julia Ablaeva, Danielle M Adams, Reza Ardehali, Adriana Arneson, C. Scott Baker, Katherine Belov, Daniel T Blumstein, Eleanor K. Bors, Charles Breeze, Robert T. Brooke, Janine L. Brown, Alex Caulton, Julie M. Cavin, Ioulia Chatzistamou, Hao Chen, Priscila Chiavellini, Oi-Wa Choi, Shannon Clarke, Joseph DeYoung, Candice K. Emmons, Stephan Emmrich, Zhe Fei, Steven H. Ferguson, Carrie J Finno, Jennifer E. Flower, Jean-Michel Gaillard, Eva Garde, Vadim N Gladyshev, Rodolfo G Goya, M. Bradley Hanson, Martin Haulena, Kelsey Herrick, 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, Marianne Lehmann, Jean-Francois Lemaitre, Andrew J. Levine, Cun Li, Xinmin Li, David TS Lin, Dana M. Lindemann, Nicholas Macoretta, Dewey Maddox, Craig O. Matkin, Julie A. Mattison, June Mergl, Jennifer J. Meudt, Gisele A. Montano, Khyobeni Mozhui, Asieh Naderi, Martina Nagy, Pritika Narayan, Peter W. Nathanielsz, Ngoc B. Nguyen, Christof Niehrs, Duncan T Odom, 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 Ritz, Jooke Robbins, Magdalena Rodriguez, Jennifer Russell, Elena Rydkina, Lindsay L. Sailer, Adam B Salmon, Akshay Sanghavi, Kyle M. Schachtschneider, Dennis Schmitt, Lars Schomacher, Lawrence B Schook, Karen E Sears, Ashley W. Seifert, Anastasia Shindyapina, Kavita Singh, Ishani Sinha, Russel G. Snell, Elham Soltanmohammadi, Matthew L. Spangler, Maria Spriggs, Karen J. Steinman, Victoria J Sugrue, Balazs Szladovits, Masaki Takasugi, Emma C. Teeling, Bill Van Bonn, Sonja C. Vernes, Harry V Vinters, Mary C. Wallingford, Nan Wang, Gerald S. Wilkinson, Robert W Williams, X. William Yang, Brent G. Young, Bohan Zhang, Zhihui Zhang, Peng Zhao, Yang Zhao, Wanding Zhou, Joseph Alan Zoller, Jason Ernst, Andrei Seluanov, Ken Raj, Vera Gorbunova, Steve Horvath

Posted 18 May 2021
bioRxiv DOI: 10.1101/2021.05.16.444078

Maximum lifespan of a species is the oldest that individuals can survive, reflecting the genetic limit of longevity in an ideal environment. Here we report methylation-based models that accurately predict maximum lifespan (r=0.89), gestational time (r=0.96), and age at sexual maturity (r=0.87), using cytosine methylation patterns collected from over 12,000 samples derived from 192 mammalian species. Our epigenetic maximum lifespan predictor corroborated the extended lifespan in growth hormone receptor knockout mice and rapamycin treated mice. Across dog breeds, epigenetic maximum lifespan correlates positively with breed lifespan but negatively with breed size. Lifespan-related cytosines are located in transcriptional regulatory regions, such as bivalent chromatin promoters and polycomb-repressed regions, which were hypomethylated in long-lived species. The epigenetic estimators of maximum lifespan and other life history traits will be useful for characterizing understudied species and for identifying interventions that extend lifespan.

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