Universal Pan-Mammalian Clock Has Been Created.

At UCLA David Geffen School of Medicine and UCLA Health, an international research team was led by scientists who published two articles outlining DNA changes. These changes, found to be shared across human history and other mammals, are linked to life span and various other traits.

The close association between the life spans of mammals and chemical modifications of the DNA molecule, particularly termed as epigenetics or more precisely, methylation, has been uncovered. Essentially, species with longer life spans showcase more pronounced DNA methylation landscapes, while those with shorter life spans display flatter and less distinct methylation patterns.

Both articles were authored by Steve Horvath, PhD, ScD, an expert on the aging process and a professor in human genetics and biostatistics at UCLA.

Insights were provided by Jason Ernst, a professor of biological chemistry, computer science, and computational medicine at UCLA, regarding the technology devised to measure DNA methylation levels across mammals. The contributions of tissue samples from a large consortium of researchers led to the creation of a distinct dataset. This dataset, when analyzed using advanced computational and statistical tools, revealed a deeper understanding of the connection between DNA methylation, life span, aging, and other biological processes among mammals.

Two studies, one published in Science and the other in Nature Aging, concentrate on DNA methylation, specifically cytosine methylation, a chemical alteration of cytosine, one of the fundamental elements of the DNA molecule.

DNA methylation serves as a mechanism through which cells regulate gene expression, either activating or deactivating genes. In these studies, the researchers directed their attention to the differences in DNA methylation among species in locations where the DNA sequence is typically uniform.

In examining the impacts of DNA methylation, methylation data from over 15,000 animal tissue samples across 348 mammalian species was collected and analyzed by the Mammalian Methylation Consortium, a group comprising nearly 200 researchers. Their findings revealed a close alignment between changes in methylation profiles and evolutionary genetic alterations. This underscores the interconnected evolution of the genome and the epigenome, which significantly influences the biological traits and characteristics of various mammalian species.

Key discoveries from the Science study

• Methylation, marked by its epigenetic imprints, demonstrates a significant correlation with the maximum life span across mammalian species. Professor Horvath likened methylation profiles on the DNA molecule to terrains with peaks and troughs, noting that species with longer life spans exhibit more distinct peaks and valleys. These are developed during prolonged gestation and development periods. On the contrary, shorter-lived species, with shorter gestation periods and rapid development, possess cells with a flatter, less clearly defined methylation landscape.
• The maximum life span of a species links to specific developmental processes, indicated by the involvement of particular genes and genetic transcription factors.
• Cytosines showing correlation between their methylation levels and maximum life span differ from those influenced by chronological age. This suggests that molecular pathways related to the average life span within a species are separate from those determining the species’ maximum life span.
• Evolutionary forces impact not just at the genetic level but also at the epigenetic level. The authors highlight that their results showcase DNA methylation’s exposure to evolutionary pressures and selection. They have made their database public for use by other researchers.

A subset of the database was utilized by Horvath and the consortium researchers to examine the methylation profiles of 185 mammal species. They identified alterations in methylation levels occurring across all mammals as they age. This led to the development of a “universal pan-mammalian clock,” a mathematical formula capable of accurately estimating age in all mammalian species. The study outcomes have been published in Nature Aging.

In 2011, Horvath and a team from UCLA introduced the idea of an epigenetic clock for age estimation, using human saliva samples. Two years later, Horvath demonstrated that cytosine methylation could form the basis of a mathematical model to estimate age across various human tissues. This recent work, outlining the concept of universal clocks, illustrates that a single formula can precisely estimate age across mammalian tissues and species.

Abstract

Using DNA methylation profiles (n = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in HOXL subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species.

https://www.science.org/doi/10.1126/science.abq5693

Findings of the Nature Aging study

• The pan-mammalian clocks maintain their high accuracy consistently across species with varying life spans, encompassing short-lived creatures like mice and rats, as well as long-lived beings such as humans, bats, and whales.
• These universal pan-mammalian clocks serve as predictors of mortality risk in both humans and mice, indicating their potential value in preclinical studies. Therefore, an intervention that reverses epigenetic age in a mouse, as indicated by the clock, might also be applicable to humans.
• Specific regions within the genetic material of cells were identified by the study, showing either an increase or decrease in methylation as chronological age advances.
• The research demonstrated the involvement of developmental genes in the operation of epigenetic clocks.
• It established a connection between developmental pathways and the effects of chronological aging and tissue deterioration. This challenges the long-held notion that aging results exclusively from random cellular damage accumulating over time. Instead, the epigenetic facets of aging seem to follow a predetermined “program.”
• The discovery of pan-mammalian clocks presents compelling evidence that aging processes are evolutionarily conserved, remaining consistent over time, and closely intertwined with developmental processes across all mammalian species.

Abstract

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.

https://www.nature.com/articles/s43587-023-00462-6