With updates and novel iterations to the “epigenetic clock” occurring at a pace faster than our smartwatches, it’s about time a new player emerged in the world of epigenetic clocks. Not only can these specialist timepieces keep track of our chronological age, but they can also tell us how environmental factors affect the pace of the epigenetic clock. While a major player in the keeping of epigenetic time, Horvath’s epigenetic clock is limited by a lack of understanding of the significance of the CpG methylation sites involved and the controlling mechanism. Furthermore, the methylation clock sites lack interspecies conservation.
These problems led Meng Wang and Bernardo Lemos (Harvard, USA) to make a timely inquiry into the existence of an epigenetic clock based on methylation of ribosomal (r)DNA, a highly-conserved segment of the genome. rDNA localizes the nucleolus and studies have revealed that aging correlates to an increase in nucleolar size and activity; however, DNA methylation acts to silence rDNA expression and thereby regulate nucleolar activity, as well as cellular metabolism, heterochromatin maintenance, and genome integrity. Therefore, rDNA methylation levels may track the aging process.
The duo began by analyzing a published data set of whole blood reduced representative bisulfite sequencing in mice aged between 0.67 to 35 months and applying statistical modeling. Specifically, the team generated two randomized equal-sized sets from said data and applied an elastic-net regression model to the DNA methylation sites (at CpGs) at a read depth of ≥50.
Here’s what the time-keepers found while checking out the tempo of theirnew epigenetic clock:
- 620 CpG methylation sites in rDNA display a positive correlation of methylation with age
- In comparison, analysis of genome-wide patterns of CpG DNA methylation during aging suggests a bias toward loss of DNA methylation with age
- Modeling efforts to examine the error between predicted and observed ages as well as the correlation between rDNA methylation and chronological age in mice provide evidence of a robust overall fit
- This data establishes that rDNA methylation accurately predicts age within species
- Both mice undergoing caloric restriction (extends lifespan/delays aging) and engineered slow-aging mice display reductions in rDNAm age compared to wild-type, thereby confirming the utility of the rDNA methylation clock
- Finally, analysis of data from dog, wolf, and human suggests evolutionary conservation of the rDNA methylation clock
The authors posit that rDNA methylation clock may represent a universal marker of aging applicable to a wide range of studies by reflecting the conserved functions of the nucleolus during aging. Importantly, the due also provide a mechanism: DNA methylation counteracts increased nucleolar size and rDNA transcription and, therefore, may serve as an excellent proxy to determine biological age.
Senior author Bernardo Lemos shares, “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.”
For more on how the ribosomal DNA methylation clock keeps aging research ticking over, make haste and see all the details over at Genome Research, February 2019.