A Ribosomal DNA Epigenetic Clock is an Unexpectedly Accurate Measure of Age

Epigenetic clocks are a weighted combination of DNA methylation at specific sites on the genome. Modern processing power allowed the association between these algorithms and aging to be reverse engineered, but it remains an open question as to what exactly is being measured. What underlying processes of aging are reflected by these characteristic epigenetic changes? All of them? Some of them? Some more than others? No-one knows in certainty, though the specific genes and proteins involved offer some suggestions. Until researchers have a better idea on that front, it is hard to use these clocks in the way we all want them to be used: to greatly speed up development of rejuvenation therapies. If it was possible to take a measure, apply a therapy, and then within days or a month at most take a second measure, and on that basis declare whether or not a particular approach works, then the assessment of potential methods of rejuvenation could proceed quite rapidly indeed.

Epigenetic clocks are evolving as researchers explore this association between DNA methylation and aging. The most interesting aspect of the new clock noted below is that only a tiny portion of the genome is involved. Even though it is apparently very similar in diverse species, to me this sounds like there is an even greater risk that the clock only measures a small slice of the many important processes of aging, and thus won't be all that helpful for the development of rejuvenation therapies. In a world without the ability to intervene in specific processes of aging, all of those processes in any given individual tend to be aligned with one another. But if just one of those processes is reversed - such as by clearance of senescent cells - then assessment will become a problem if epigenetic clocks behave unpredictably in this sort of scenario.

In practice, what is going to happen is that measures of aging and rejuvenation will be developed in parallel to the development of rejuvenation therapies. Perhaps epigenetic clocks will be increasingly calibrated to report on the outcome of clearance of senescent cells, for example. This seems likely, as the industry will want something more than just counts of cells and reversal of symptoms for one specific age-related disease to show that they are affecting the course of aging in a profound way. But that tailored epigenetic clock may well turn out to be useless for, say, assessing the effects of cross-link breaking on the progression of aging. Nothing is simple in biochemistry. We might hope for a universal assessment of age to turn up sometime soon, to speed up research and development, but it may well be the case that the only practical way to build such a measure is to first make significant progress in all of the areas of the full SENS program of rejuvenation therapies.

Uncovering a "smoking gun" of biological aging

Researchers looked at ribosomal DNA (rDNA), the most active segment of the genome and one which has also been mechanistically linked to aging in a number of previous studies. They hypothesized that the rDNA is a "smoking gun" in the genomic control of aging and might harbor a previously unrecognized clock. To explore this concept, 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 kilobases) but essential and highly active segment of the genome, as a novel marker of age.

Analysis of genome-wide data sets from mice, dogs, and humans indicated that the researchers' hypothesis had merit: numerous CpGs in the rDNA exhibited signs of increased methylation - a result of aging. To further test the clock, they studied data from 14-week-old mice that responded to calorie restriction, a known intervention that promotes longevity. The mice that were placed on a calorie-restricted regimen showed significant reductions in rDNA methylation at CpG sites compared with mice that did not have their caloric intake restricted. Moreover, calorie-restricted mice showed rDNA age that was younger than their chronological 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 novel 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 to serve as a widely applicable predictor of individual age that can be calibrated for all mammalian species.

Ribosomal DNA harbors an evolutionarily conserved clock of biological aging

The ribosomal DNA (rDNA) is the most evolutionarily conserved segment of the genome and gives origin to the nucleolus, an energy intensive nuclear organelle and major hub influencing myriad molecular processes from cellular metabolism to epigenetic states of the genome. The rDNA/nucleolus has been directly and mechanistically implicated in aging and longevity in organisms as diverse as yeasts, Drosophila, and humans. The rDNA is also a significant target of DNA methylation that silences supernumerary rDNA units and regulates nucleolar activity.

Here, we introduce an age clock built exclusively with CpG methylation within the rDNA. The ribosomal clock is sufficient to accurately estimate individual age within species, is responsive to genetic and environmental interventions that modulate life-span, and operates across species as distant as humans, mice, and dogs. Further analyses revealed a significant excess of age-associated hypermethylation in the rDNA relative to other segments of the genome, and which forms the basis of the rDNA clock. 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.

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