Researchers at UCLA discovered a strong correlation between DNA methylation patterns and mammalian life expectancy. Through comprehensive analysis, they discovered that DNA methylation, an epigenetic modification, plays an essential role in aging, with its impacts visible throughout species and intimately connected to developmental and evolutionary processes.
UCLA scientists lead groundbreaking research studies on mammalian aging and life expectancy.
Scientists from the UCLA David Geffen School of Medicine and UCLA Health led an international research team that released 2 articles detailing modifications in DNA– changes that researchers found are shared by people and other mammals throughout history and are connected with life span and many other qualities.
” Weve discovered that the life expectancy of mammals are closely related to chemical adjustments of the DNA particle, specifically called epigenetics, or more precisely, methylation. In essence, mammals with longer life periods display more noticable DNA methylation landscapes, whereas those of shorter-lived species have more suppressed, flatter methylation patterns,” said the senior author of both short articles, Steve Horvath, Ph.D., ScD, a professional on the aging procedure and a teacher in human genetics and biostatistics at UCLA at the time the research studies were performed.
Jason Ernst, a professor of biological chemistry, computer technology, and computational medicine at UCLA, said, “The technology we developed to measure DNA methylation levels throughout mammals together with the tissue sample contributions from a big consortium of researchers led to the production of a highly unique data set, which, when analyzed with advanced computational and statistical tools, revealed a deeper understanding of the relationship between DNA methylation, life expectancy, aging, and other biological procedures across mammals.”
The studies, one published in Science and the other in Nature Aging, focus on DNA methylation, or cytosine methylation, a chemical adjustment of cytosine, one of the 4 foundation of the DNA particle.
DNA methylation is a system by which cells can manage gene expression– turning genes on or off. In these research studies, the scientists concentrated on DNA methylation distinctions throughout species at areas where the DNA series is normally the very same.
This circle plot shows the connection between age and DNA methylation age for various types estimated by the two universal clocks developed. Credit: Ake Lu and Steve Horvath
To study the effects of DNA methylation, the almost 200 researchers– jointly referred to as the Mammalian Methylation Consortium– collected and evaluated methylation information from more than 15,000 animal tissue samples covering 348 mammalian species. They discovered that changes in methylation profiles carefully parallel changes in genetics through evolution, demonstrating that there is a linked evolution of the genome and the epigenome that influences the biological attributes and traits of different mammalian species.
Amongst the Science studys findings:
Methylation, as evidenced by the epigenetic “marks” it leaves, bears a substantial connection with optimal life period throughout mammalian species. Looking at methylation profiles on the DNA molecule as terrain with troughs and peaks, Horvath commented that types with long lives have popular peaks and valleys, developed throughout extended gestation and development periods. On the other hand, brief species have short pregnancy durations and fast advancement, resulting in cells with a flatter, less-defined methylation landscape.
The maximum life period of a types is associated with specific developmental procedures, as suggested by the involvement of particular genes and hereditary transcription factors.
Cytosines whose methylation levels associate with optimal life expectancy vary from those that change with chronological age, recommending that molecular paths relating to typical life period within a types stand out from those identifying the species maximum life expectancy.
Advancement acts not just at the genetic level, however also at the epigenetic level. “Our outcomes show that DNA methylation is subjected to evolutionary pressures and choice,” said the authors, whose database has been revealed for other scientists.
Horvath and the consortium researchers utilized a subset of the database to study the methylation profiles of 185 types of mammals. Identifying changes in methylation levels that accompany age throughout all mammals, they developed a “universal pan-mammalian clock,” a mathematical formula that can accurately approximate age in all mammalian species. The outcomes of this study are published in Nature Aging.
Horvath and a UCLA group introduced the principle of an epigenetic clock for age measurement, utilizing human saliva samples, in 2011. Two years later, Horvath demonstrated that cytosine methylation makes it possible for the production of a mathematical model for approximating age across all human tissues. The brand-new work, which explains universal clocks, shows that a single formula can properly approximate age throughout mammalian tissues and types.
Among the Nature Aging studys findings:
Methylation, as evidenced by the epigenetic “marks” it leaves, bears a considerable correlation with maximum life span across mammalian types. Looking at methylation profiles on the DNA particle as terrain with troughs and peaks, Horvath commented that species with long lives have prominent peaks and valleys, established during extended pregnancy and advancement durations. Horvath and the consortium scientists utilized a subset of the database to study the methylation profiles of 185 species of mammals. Determining changes in methylation levels that occur with age throughout all mammals, they established a “universal pan-mammalian clock,” a mathematical formula that can properly approximate age in all mammalian types. Competing interests Nature Aging paper: The Regents of the University of California filed a patent application (publication number WO2020150705) related to this work on which S.H., A. Arneson and J.E. are called innovators.
Recommendations: “DNA methylation networks underlying mammalian qualities” by Amin Haghani, Caesar Z. Li, Todd R. Robeck, Joshua Zhang, Ake T. Lu, Julia Ablaeva, Victoria A. Acosta-Rodríguez, Danielle M. Adams, Abdulaziz N. Alagaili, Javier Almunia, Ajoy Aloysius, Nabil M.S. Amor, Reza Ardehali, Adriana Arneson, C. Scott Baker, Gareth Banks, Katherine Belov, Nigel C. Bennett, Peter Black, Daniel T. Blumstein, Eleanor K. Bors, Charles E. Breeze, Robert T. Brooke, Janine L. Brown, Gerald Carter, Alex Caulton, Julie M. Cavin, Lisa Chakrabarti, Ioulia Chatzistamou, Andreas S. Chavez, Hao Chen, Kaiyang Cheng, Priscila Chiavellini, Oi-Wa Choi, Shannon Clarke, Joseph A. Cook, Lisa N. Cooper, Marie-Laurence Cossette, Joanna Day, Joseph DeYoung, Stacy Dirocco, Christopher Dold, Jonathan L. Dunnum, Erin E. Ehmke, Candice K. Emmons, Stephan Emmrich, Ebru Erbay, Claire Erlacher-Reid, Chris G. Faulkes, Zhe Fei, Steven H. Ferguson, Carrie J. Finno, Jennifer E. Flower, Jean-Michel Gaillard, Eva Garde, Livia Gerber, Vadim N. Gladyshev, Rodolfo G. Goya, Matthew J Grant, Carla B. Green, M. Bradley Hanson, Daniel W. Hart, Martin Haulena, Kelsey Herrick, Andrew N. Hogan, Carolyn J. Hogg, Timothy A. Hore, Taosheng Huang, Juan Carlos Izpisua Belmonte, 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, Michael Krützen, Soo Bin Kwon, Brenda Larison, Sang-Goo Lee, Marianne Lehmann, Jean-François Lemaître, Andrew J. Levine, Xinmin Li, Cun Li, Andrea R. Lim, David T. S. Lin, Dana M. Lindemann, Schuyler W. Liphardt, Thomas J. Little, Nicholas Macoretta, Dewey Maddox, Craig O. Matkin, Julie A. Mattison, Matthew McClure, June Mergl, Jennifer J. Meudt, Gisele A. Montano, Khyobeni Mozhui, Jason Munshi-South, William J. Murphy, Asieh Naderi, Martina Nagy, Pritika Narayan, Peter W. Nathanielsz, Ngoc B. Nguyen, Christof Niehrs, Batsaikhan Nyamsuren, Justine K. OBrien, Perrie OTierney Ginn, Duncan T Odom, Alexander G. Ophir, Steve Osborn, Elaine A. Ostrander, Kim M. Parsons, Kimberly C. Paul, Amy B. Pedersen, Matteo Pellegrini, Katharina J. Peters, Jessica L. Petersen, Darren W. Pietersen, Gabriela M. Pinho, Jocelyn Plassais, Jesse R. Poganik, Natalia A. Prado, Pradeep Reddy, 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, Ashley W. Seifert, Aaron B.A. Shafer, Anastasia V. Shindyapina, Melanie Simmons, Kavita Singh, Ishani Sinha, Jesse Slone, Russel G. Snell, Elham Soltanmohammadi, Matthew L. Spangler, Maria Spriggs, Lydia Staggs, Nancy Stedman, Karen J. Steinman, Donald T Stewart, Victoria J. Sugrue, Balazs Szladovits, Joseph S. Takahashi, Masaki Takasugi, Emma C. Teeling, Michael J. Thompson, Bill Van Bonn, Sonja C. Vernes, Diego Villar, Harry V. Vinters, Ha Vu, Mary C. Wallingford, Nan Wang, Gerald S. Wilkinson, Robert W. Williams, Qi Yan, Mingjia Yao, Brent G. Young, Bohan Zhang, Zhihui Zhang, Yang Zhao, Peng Zhao, Wanding Zhou, Joseph A. Zoller, Jason Ernst, Andrei Seluanov, Vera Gorbunova, X. William Yang, Ken Raj and Steve Horvath, 11 August 2023, Science.DOI: 10.1126/ science.abq5693.
” Universal DNA methylation age across mammalian tissues” by A. T. Lu, Z. Fei, A. Haghani, T. R. Robeck, J. A. Zoller, C. Z. Li, R. Lowe, Q. Yan, J. Zhang, H. Vu, J. Ablaeva, V. A. Acosta-Rodriguez, D. M. Adams, J. Almunia, A. Aloysius, R. Ardehali, A. Arneson, C. S. Baker, G. Banks, K. Belov, N. C. Bennett, P. Black, D. T. Blumstein, E. K. Bors, C. E. Breeze, R. T. Brooke, J. L. Brown, G. G. Carter, A. Caulton, J. M. Cavin, L. Chakrabarti, I. Chatzistamou, H. Chen, K. Cheng, P. Chiavellini, O. W. Choi, S. M. Clarke, L. N. Cooper, M. L. Cossette, J. Day, J. DeYoung, S. DiRocco, C. Dold, E. E. Ehmke, C. K. Emmons, S. Emmrich, E. Erbay, C. Erlacher-Reid, C. G. Faulkes, S. H. Ferguson, C. J. Finno, J. E. Flower, J. M. Gaillard, E. Garde, L. Gerber, V. N. Gladyshev, V. Gorbunova, R. G. Goya, M. J. Grant, C. B. Green, E. N. Hales, M. B. Hanson, D. W. Hart, M. Haulena, K. Herrick, A. N. Hogan, C. J. Hogg, T. A. Hore, T. Huang, J. C. Izpisua Belmonte, A. J. Jasinska, G. Jones, E. Jourdain, O. Kashpur, H. Katcher, E. Katsumata, V. Kaza, H. Kiaris, M. S. Kobor, P. Kordowitzki, W. R. Koski, M. Krützen, S. B. Kwon, B. Larison, S. G. Lee, M. Lehmann, J. F. Lemaitre, A. J. Levine, C. Li, X. Li, A. R. Lim, D. T. S. Lin, D. M. Lindemann, T. J. Little, N. Macoretta, D. Maddox, C. O. Matkin, J. A. Mattison, M. McClure, J. Mergl, J. J. Meudt, G. A. Montano, K. Mozhui, J. Munshi-South, A. Naderi, M. Nagy, P. Narayan, P. W. Nathanielsz, N. B. Nguyen, C. Niehrs, J. K. OBrien, P. OTierney Ginn, D. T. Odom, A. G. Ophir, S. Osborn, E. A. Ostrander, K. M. Parsons, K. C. Paul, M. Pellegrini, K. J. Peters, A. B. Pedersen, J. L. Petersen, D. W. Pietersen, G. M. Pinho, J. Plassais, J. R. Poganik, N. A. Prado, P. Reddy, B. Rey, B. R. Ritz, J. Robbins, M. Rodriguez, J. Russell, E. Rydkina, L. L. Sailer, A. B. Salmon, A. Sanghavi, K. M. Schachtschneider, D. Schmitt, T. Schmitt, L. Schomacher, L. B. Schook, K. E. Sears, A. W. Seifert, A. Seluanov, A. B. A. Shafer, D. Shanmuganayagam, A. V. Shindyapina, M. Simmons, K. Singh, I. Sinha, J. Slone, R. G. Snell, E. Soltanmaohammadi, M. L. Spangler, M. C. Spriggs, L. Staggs, N. Stedman, K. J. Steinman, D. T. Stewart, V. J. Sugrue, B. Szladovits, J. S. Takahashi, M. Takasugi, E. C. Teeling, M. J. Thompson, B. Van Bonn, S. C. Vernes, D. Villar, H. V. Vinters, M. C. Wallingford, N. Wang, R. K. Wayne, G. S. Wilkinson, C. K. Williams, R. W. Williams, X. W. Yang, M. Yao, B. G. Young, B. Zhang, Z. Zhang, P. Zhao, Y. Zhao, W. Zhou, J. Zimmermann, J. Ernst, K. Raj and S. Horvath, 10 August 2023, Nature Aging.DOI: 10.1038/ s43587-023-00462-6.
Contending interests Science paper: S.H., A.A., and J.E. are inventors on patent/patent application number WO2020150705 held/submitted by the University of California, Los Angeles that covers the mammalian methylation variety technology. S.H. and R.T.B. are creators of the not-for-profit Epigenetic Clock Development Foundation, which has accredited numerous patents from UC Regents and distributes the mammalian methylation variety.
Contending interests Nature Aging paper: The Regents of the University of California submitted a patent application (publication number WO2020150705) related to this work on which S.H., A. Arneson and J.E. are called innovators. S.H. and R.T.B. are creators of the non-profit Epigenetic Clock Development Foundation, which has actually certified several patents from UC Regents, and disperses the mammalian methylation selection. The staying authors declare no contending interests.
The pan-mammalian clocks preserve their high precision throughout types with differing life expectancy, from temporary mice and rats to long-lived humans, bats, and whales.
The universal pan-mammalian clocks are predictors of death threat in human beings and mice, which recommends they might show important for preclinical research studies. An intervention that reverses epigenetic age in a mouse, according to the clock, may be applicable to humans.
The research study recognized particular areas in the genetic material of cells that either gain or lose methylation with sequential age.
The research study revealed that developmental genes play a role in the performance of epigenetic clocks.
The research study connects developmental paths with sequential aging impacts and tissue deterioration. This refutes the long-standing belief that aging is driven exclusively by random cellular damage that accumulates over time. Rather, the epigenetic elements of aging follow a predetermined “program.”.
The discovery of the pan-mammalian clocks offers compelling evidence that aging procedures are evolutionarily saved– staying constant through time– and are closely related to developmental procedures throughout all mammalian types.