Finding our genomic clockwork

Harvard researchers discover a biomarker that can determine both chronological and biological age.

A team of scientists at the Harvard Gazette has recently discovered a new type of ribosomal DNA (rDNA) clock as a novel biomarker of aging based on the rDNA, a segment of the genome that previously has been mechanistically linked to aging.

This newly discovered rDNA could be used to precisely identify an individual’s chronological and biological age. It has potentially wide applications, including measuring how exposures to certain pollutants or dietary interventions accelerate or slow aging in a diversity of species, including mice and humans.

Senior author Bernardo Lemos, associate professor of environmental epigenetics said, “We have hopes that the ribosomal clock will provide new insights into the impact of the environment and personal choices on long-term health. Determining biological age is a central step to understanding fundamental aspects of aging as well as developing tools to inform personal and public health choices.”

There are two types of age: chronological age, or the number of years a person or animal has lived, and biological age, which accounts for lifestyle factors that can shorten or extend lifespan, including diet, exercise, and environmental exposures. Overall, biological age has been shown to be a better predictor of all-cause mortality and disease onset than chronological age.

For the study, scientists observed rDNA, the most active segment of the genome and one that has also been mechanistically linked to aging in a number of previous studies.

Scientists hypothesized that the rDNA is a “smoking gun” in the genomic control of aging, and might harbor a previously unrecognized clock. To test the idea, they examined epigenetic chemical alterations (also known as DNA methylation) in CpG sites, where a cytosine nucleotide is followed by a guanine nucleotide. The study homed in on the rDNA, a small (13-kilobase) but essential and highly active segment of the genome, as a novel marker of age.

Examination of genome-wide data sets from mice, dogs, and people showed that the speculation had legitimacy: Numerous CpGs in the rDNA displayed indications of expanded methylation — a result of aging. To additionally test the clock, they contemplated information from 14-week-old mice that reacted to calorie confinement, a known mediation that advances life span.

The mice that were set on a calorie-confined routine demonstrated huge decreases in rDNA methylation at CpG destinations contrasted and mice that did not have their eating diet limited. In addition, calorie-limited mice indicated rDNA age that was more youthful than their ordered age.

The researchers were surprised that assessing methylation in a small segment of the mammalian genome yielded clocks as accurate as clocks built from hundreds of thousands of sites along the genome. They noted that their approach could prove faster and more cost-effective at determining biological and chronological age than current methods of surveying the dispersed sites in the genome. The findings underscore the fundamental role of rDNA in aging and highlight its potential as a widely applicable predictor of age that can be calibrated for all mammalian species.

Importantly, the clocks respond to interventions, which could allow scientists to study how biological age responds to environmental exposures and lifestyle choices. Ascertaining an accurate biological age can indicate of how much better or worse an individual is doing relative to the general population, and could potentially help monitor whether that person is at heightened risk of death or a given disease.

The study was published online today in Genome Research.

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