A Universal Epigenetic Aging Clock for All Mammalian Species

Epigenetic modifications to the nuclear genome, such as the addition of methyl groups to CpG sites, known as DNA methylation, adjust the structure of double-stranded DNA. That structure determines which gene sequences are accessible to transcription machinery, the first step in producing proteins. Thus epigenetics drives gene expression, and gene expression drives the behavior of cells. It is a feedback loop between environment, cell behavior, and epigenetics. The pattern of epigenetic modifications changes constantly in response to circumstances, but some changes are characteristic of aging. When discovered, this led to the construction of the first epigenetic clocks to measure chronological age and then biological age.

More than a decade later, epigenetic clocks are still very much a work in progress, in the sense that it is not well understood as to how the fundamental mechanisms of aging connect to the methylation of specific CpG sites on the genome. It is presently impossible to say whether any given clock (epigenetic or otherwise) will accurately reflect the effects of a given intervention on future life span and risk of age-related disease. Clocks have also been tissue and species specific, at least until now. Researchers have now mined data from many different species in order to produce a cross-species clock that can be applied to all mammals.

Looking past that advance, it is perhaps more interesting to note that the researchers examining DNA methylation across hundreds of mammalian species found that methylation sites whose status changes with age are largely distinct from methylation sites where status correlates with species life span. This distinction between epigenetic mechanisms of individual longevity and epigenetic mechanisms of species longevity is reinforced by the work of other research groups examining omics data in multiple mammalian species. One hypothesis that we might take away from this is that there is a sizable untapped set of mechanisms that might be targeted to extend healthy life span. Given omics signatures from long-lived mammals that are associated with species life span rather than individual aging, one might perform screening to find novel classes of interventions that slow aging in shorter-lived mammals.

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

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.

Methylation, as evidenced by the epigenetic "marks" it leaves, bears a substantial correlation with maximum life span across mammalian species. 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.

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.

DNA methylation networks underlying mammalian traits

Comparative epigenomics is an emerging field that combines epigenetic signatures with phylogenetic relationships to elucidate species characteristics such as maximum life span. For this study, we generated cytosine DNA methylation (DNAm) profiles (n = 15,456) from 348 mammalian species using a methylation array platform that targets highly conserved cytosines. We first tested whether DNAm levels in highly conserved cytosines captured phylogenetic relationships among species. We constructed phyloepigenetic trees that paralleled the traditional phylogeny. To avoid potential confounding by different tissue types, we generated tissue-specific phyloepigenetic trees. The high phyloepigenetic-phylogenetic congruence is due to differences in methylation levels and is not confounded by sequence conservation.

We then interrogated the extent to which DNA methylation associates with specific biological traits. Both the epigenome-wide association analysis (EWAS) and eigengene-based analysis identified methylation signatures of maximum life span, and most of these were independent of aging, presumably set at birth, and could be stable predictors of life span at any point in life. Several CpGs that are more highly methylated in long-lived species are located near HOXL subclass homeoboxes and other genes that play a role in morphogenesis and development. Some of these life span-related CpGs are located next to genes that are also implicated in our analysis of upstream regulators (e.g., ASCL1 and SMAD6). CpGs with methylation levels that are inversely related to life span are enriched in transcriptional start site and promoter flanking associated chromatin states. Genes located in chromatin state TSS1 are constitutively active and enriched for nucleic acid metabolic processes. This suggests that long-living species evolved mechanisms that maintain low methylation levels in these chromatin states that would favor higher expression levels of genes essential for an organism's survival.


This seems like a big step forward in the field of aging clocks - an achievement that will now accelerate progress in multiple ways.

Posted by: Michael Geisen at August 20th, 2023 5:30 PM
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