An international research team led by scientists from UCLA David Geffen School of Medicine and UCLA Health published two articles describing changes in DNA that were discovered to have occurred in both humans and other mammals throughout history and to be related to life span and a variety of other traits.
“We’ve found that methylation, or epigenetics, is a more precise term for the chemical alterations of the DNA molecule that are intimately related to the life lengths of mammals. In essence, mammals from species with longer life spans show more pronounced DNA methylation landscapes, whereas those from species with shorter life spans have more subdued, flatter methylation patterns,” said Steve Horvath, Ph.D., ScD, senior author of both articles and an expert on aging who was a professor of human genetics and biostatistics at UCLA at the time the studies were conducted.
“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 s processes, and disease,” said Jason Ernst, a professor of biological chemistry, computer science, and computational medicine at UCLA.
The two studies—one appearing in Science and the other in Nature Aging—concentrate on DNA methylation, also known as cytosine methylation, a chemical alteration of cytosine, one of the four components of the DNA molecule.
Cells can control gene expression—turning genes on or off—by means of DNA methylation. These studies concentrated on DNA methylation variations between species in regions of the genome where the DNA sequence is often the same.
The Mammalian Methylation Consortium, a group of about 200 researchers studying the effects of DNA methylation, gathered and examined methylation data from more than 15,000 animal tissue samples from 348 mammalian species. They discovered that variations in methylation profiles closely resemble changes in genetic makeup over the course of evolution, showing that the evolution of the genome and the epigenome are interwoven and affect the biological traits and characteristics of many mammalian species.
Findings from the Science study include:
Methylation significantly correlates with the maximum life span across mammalian species, as shown by the epigenetic “marks” it leaves. Horvath observed that animals with long lifespans exhibit notable peaks and valleys, developed through prolonged gestation and development periods, while examining methylation profiles on the DNA molecule as topography with peaks and troughs. Contrarily, cells from short-lived species have a flatter, less distinct methylation landscape because of their brief gestation periods and quick growth.
The participation of specific genes and genetic transcription factors suggests that a species’ maximal life span is linked to particular developmental processes.
It is possible that the molecular processes governing average life span within a species are different from those governing the species’ maximum life span. This is because cytosines whose methylation levels correlate with maximum life span differ from those that alter with chronological age.
In addition to the genetic level, epigenetics also plays a role in evolution. Our findings show that DNA methylation is influenced by selection and evolutionary pressures, according to the scientists, whose database has been made available to other researchers.
To examine the methylation profiles of 185 species of animals, Horvath and the consortium’s researchers analyzed a portion of the database. They created a “universal pan-mammalian clock,” a mathematical formula that can precisely predict age in all mammalian species, after identifying changes in methylation levels that occur with age across all mammals. This study’s findings have been published in Nature Aging.
In 2011, Horvath and a team from UCLA proposed the idea of an epigenetic clock for age estimation using samples of human saliva. Horvath showed two years later that cytosine methylation makes it possible to develop a mathematical model for determining age in all human organs. The new work, which describes universal clocks, shows that an age estimation formula can be applied to all mammalian tissues and species with high accuracy.
Among the results of the Nature Aging study were:
Despite species with diverse life lengths, such as short-lived mice and rats and long-lived humans, bats, and whales, the pan-mammalian clocks maintain their great accuracy.
The fact that the universal pan-mammalian clocks can predict the likelihood of mortality in both mice and humans suggests they may be useful for preclinical research. Therefore, a treatment that delays the clock of epigenetic age in a mouse may also be effective in people.
The study pinpointed specific areas in cells’ genetic material that either experience methylation increase or loss as they age.
According to the study, epigenetic clocks are controlled by developmental genes.
The study links tissue deterioration and chronological aging effects with developmental pathways. This disproves the conventional wisdom that aging is exclusively caused by sporadic cellular damage that builds up over time. The epigenetic effects of aging, in contrast, adhere to a predetermined “program.”
The discovery of the pan-mammalian clocks offers convincing proof that aging processes are evolutionarily conserved, remaining constant over time, and are strongly connected with developmental processes in all mammalian species.