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Ribosomal DNA Methylation May Serve as Clock of Aging in Mammals

NEW YORK (GenomeWeb) – Two researchers from the Harvard T.H. Chan School of Public Health have identified ribosomal DNA (rDNA) epigenetic features that may ultimately serve as clocks for estimating biological age in humans and other mammals.

"Our observations identified an evolutionarily conserved marker of aging that is easily ascertained, grounded on nucleolar biology, and could serve as a universal marker to gauge individual age and response to interventions in humans as well as laboratory and wild organisms across a wide diversity of species," senior author Bernardo Lemos, an environmental epigenetics researcher affiliated with Harvard and the Broad Institute, and lead author Meng Wang, a research fellow wrote.

In a study published online today in Genome Research, Lemos and Wang used new and previously available whole-genome sequencing and reduced-representation bisulfite sequencing data from hundreds of mouse, dog, and human samples, searching for methylation profiles with potential ties to aging. From the mouse datasets, the researchers identified CpG sites in the rDNA that showed increased methylation with age, leading to a proposed age clock model that roughly corresponded with age in the canine and human samples they tested subsequently.

"Our study underscores the fundamental role of the ultra-conserved rDNA in aging and its ability to serve as a universal predictor of individual age that can be efficiently calibrated for a diversity of species and also be applied across species," the authors wrote.

Aging has been implicated in conditions ranging from heart disease to cancer to neurological conditions, the team noted, though prior research suggests that biological age measurements that take environmental exposures, diet, and lifestyle into account may share closer ties to age-related disease onset and mortality risk than an individual's chronological age, or actual lifespan.

The researchers speculated that rDNA may provide insights into both chronological and biological age, given its role in processes such as cellular metabolism, epigenetics, expression regulation, and nucleolar organelle biology. They suggested that rDNA, which is highly conserved, is "an ideal candidate to harbor fundamental and evolutionarily conserved aging mechanisms as well as yield widely applicable markers of aging." 

"We have hopes that the ribosomal clock will provide new insights into the impact of the environment and personal choices on long-term health," Lemos said in a statement, since "[d]etermining biological age is a central step to understanding fundamental aspects of aging as well as developing tools to inform personal and public health choices."

Starting with RRBS-based methylation profiles for mice from 16 age groups, spanning a few weeks to almost three years, Lemos and Wang identified hundreds of CpG methylation sites that seemed to track with age, including enhanced methylation at marks in rDNA coding or promoter regions — aging and rDNA methylation associations they confirmed using two more published mouse datasets.

For their subsequent experiments, the researchers came up with rDNA CpG methylation-based models for predicting chronological age in mouse training and testing sites, before expanding their rDNA methylation analyses to biological age in slow-aging mice that are missing the growth hormone receptor or mice exposed to caloric restriction regimens previously shown to stretch out lifespan and slow aging.

Both interventions were linked to lower-than-usual rDNA methylation in the aging mice, the team reported, suggesting that both chronological age and lifestyle or environmental factors can feed into the rDNA CpG methylation readout.

Methylation in rDNA appeared to coincide with aging in other mammals as well: the investigators used the rDNA clock models established in mice to predict age from RRBS profiles for dozens of dogs and wolves and from whole-genome bisulfite sequence data from human cell lines or skin samples from six adults.

"The data presented here further reveal the unique potential of using rDNA CpGs to build methylation age clocks that can be employed inter-specifically," the authors wrote. "Collectively, the ribosomal clock likely reflects conserved functions of the nucleolus during aging, can serve as a universal marker of aging, and could be deployed to aging and population studies in natural setting and wild organisms across a variety of species." 

In contrast, the authors noted that although some methylation marks across the broader mammalian genomes have been shown to correspond with aging in humans and mice, these sites "are scattered along the genome and are neither functionally related to one another nor evolutionarily conserved across species."