Global consortium creates large-scale, cross-species database and universal ‘clock’ to estimate age in all mammalian tissues

Scientists at UCLA David Geffen School of Medicine and UCLA Health led an international research team that published two articles detailing changes in DNA – changes that researchers found are shared by humans and other mammals throughout history and are associated with life span and numerous other traits.

“We’ve discovered that the life spans of mammals are closely associated with chemical modifications of the DNA molecule, specifically known as epigenetics, or more accurately, methylation. In essence, mammals with longer life spans exhibit more pronounced DNA methylation landscapes, whereas those of shorter-lived species have more subdued, flatter methylation patterns,” said the senior author of both articles, Steve Horvath, PhD, ScD, an expert on the aging process and a professor in human genetics and biostatistics at UCLA at the time the studies were conducted.

Jason Ernst, a professor of biological chemistry, computer science, and computational medicine at UCLA, said, “The technology we designed to measure DNA methylation levels across mammals along with the tissue sample contributions from a large consortium of researchers led to the production of a highly unique data set, which, when analyzed with advanced computational and statistical tools, unveiled a deeper understanding of the relationship between DNA methylation, life span, aging, and other biological processes across mammals.”

The studies, one published in Science and the other in Nature Aging, focus on DNA methylation, or cytosine methylation, a chemical modification of cytosine, one of the four building blocks of the DNA molecule.

DNA methylation is a mechanism by which cells can control gene expression – turning genes on or off. In these studies, the researchers focused on DNA methylation differences across species at locations where the DNA sequence is generally the same.

To study the effects of DNA methylation, the nearly 200 researchers – collectively known as the Mammalian Methylation Consortium – collected and analyzed methylation data from more than 15,000 animal tissue samples covering 348 mammalian species. They found that changes in methylation profiles closely parallel changes in genetics through evolution, demonstrating that there is an intertwined evolution of the genome and the epigenome that influences the biological characteristics and traits of different mammalian species.

Among the Science study’s findings:

• Methylation, as evidenced by the epigenetic “marks” it leaves, bears a substantial correlation with maximum life span across mammalian species. Looking at methylation profiles on the DNA molecule as terrain with peaks and troughs, Horvath commented that species with long lives have prominent peaks and valleys, developed during extended gestation and development periods. In contrast, short-lived species have short gestation periods and rapid development, resulting in cells with a flatter, less-defined methylation landscape.
• Maximum life span of a species is associated with specific developmental processes, as suggested by the involvement of certain genes and genetic transcription factors.
• Cytosines whose methylation levels correlate with maximum life span differ from those that change with chronological age, suggesting that molecular pathways pertaining to average life span within a species are distinct from those determining the species’ maximum life span.
• Evolution acts not only at the genetic level, but also at the epigenetic level. “Our results demonstrate that DNA methylation is subjected to evolutionary pressures and selection,” said the authors, whose database has been made public for other researchers.

Horvath and the consortium researchers used a subset of the database to study the methylation profiles of 185 species of mammals. Identifying changes in methylation levels that occur with age across all mammals, they developed a “universal pan-mammalian clock,” a mathematical formula that can accurately estimate age in all mammalian species. Results of this study are published in Nature Aging.

Horvath and a UCLA team introduced the concept of an epigenetic clock for age measurement, using human saliva samples, in 2011. Two years later, Horvath demonstrated that cytosine methylation enables the creation of a mathematical model for estimating age across all human tissues. The new work, which describes universal clocks, demonstrates that a single formula can accurately estimate age across mammalian tissues and species.

Among the Nature Aging study’s findings:

• The pan-mammalian clocks maintain their high accuracy across species with varying life spans, from short-lived mice and rats to long-lived humans, bats and whales.
• The universal pan-mammalian clocks are predictors of mortality risk in humans and mice, which suggests they could prove valuable for preclinical studies. Therefore, an intervention that reverses epigenetic age in a mouse, according to the clock, might be applicable to humans as well.
• The study identified specific regions in the genetic material of cells that either gain or lose methylation with chronological age.
• The research revealed that developmental genes play a role in the functioning of epigenetic clocks.
• The research connects developmental pathways with chronological aging effects and tissue degradation. This refutes the long-standing belief that aging is driven solely by random cellular damage that accumulates over time. Instead, the epigenetic aspects of aging follow a predetermined “program.”
• The discovery of the pan-mammalian clocks provides compelling evidence that aging processes are evolutionarily conserved – remaining consistent through time – and are closely linked with developmental processes across all mammalian species.

Authors Horvath, the principal investigator of the Mammalian Methylation Consortium, is the senior author of both papers. First authors of the Science article are Amin Haghani, PhD, and Caesar Z. Li, PhD, both of UCLA. First authors of the Nature Aging paper are Ake T. Lu, PhD, and Zhe Fei, PhD, both of UCLA. Numerous other UCLA faculty members and their students, postdoctoral fellows and research staff members are co-authors. Among them are Jason Ernst, PhD; Dr. William Yang MD, PhD; Karen Sears, PhD; and Ren Larison, PhD. Complete lists of all authors and affiliations are published with the articles.

Funding See the articles for full funding information.

Competing 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 array technology. S.H. and R.T.B. are founders of the nonprofit Epigenetic Clock Development Foundation, which has licensed several patents from UC Regents and distributes the mammalian methylation array.

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 named inventors. S.H. and R.T.B. are founders of the non-profit Epigenetic Clock Development Foundation, which has licensed several patents from UC Regents, and distributes the mammalian methylation array. The remaining authors declare no competing interests.

Article Science: A. Haghani et al., DNA methylation networks underlying mammalian traits Science 381, eabq5693 (2023). DOI https://doi.org/10.1126/science.abq5693

Article Nature Aging: A. T. Lu, Z. Fei, A. Haghani et al. Universal DNA methylation age across mammalian tissues. Nat Aging (2023). DOI https://doi.org/10.1038/s43587-023-00462-6

Graphic: Circle plot shows the correlation between age and DNA methylation age for various species estimated by the two universal clocks developed. Credit: Ake Lu and Steve Horvath https://drive.google.com/file/d/1Lxi58Irv7QPqDDYhPMglNBLMV9NTzs74/view?usp=sharing