While it may seem like it’s harder to keep up with epigenetic clocks than with the Kardashians, this is one you’re not going to want to miss. Many epigenetic clocks people use to assess aging are built on the DNA methylation status of a few CpGs, and it’s unclear how these sites are related to aging. Now, a punctual team reports on the PRC2-AgeIndex, a genome-wide marker of gain-of-methylation at CpGs that could monitor aging and the effects of fountain-of-youth anti-aging treatments.
Loss of DNA methylation in aging has been well studied, but people have not paid as much attention to DNAm gain. Studies show that polycomb repressive complex 2 (PRC2) is often bound at low-methylated regions (LMRs) at repressed promoters, and CpGs that gain methylation with aging and cancer typically have sites for PRC2 to bind.
Michael Snyder and Vittorio Sebastiano’s teams (Stanford University) and groups at various institutions wanted to “spring ahead” and take the next step, turning these biologically relevant regions into an approach to measure these methylation changes genome-wide and by age. They analyzed young and old human CD4+ and epidermis tissue, as well as embryonic stem cells (hESCs) with whole-genome bisulfite sequencing. Here’s what they found:
- The three tissue types have many LMRs in common
- PRC2 core subunits bind to a subset of LMRs
- Most of the LMRs that are bound by PRC2 in hESCs are methylated in the older samples
- A similar, though not as strong, trend occurs in mice
- More than 90% of the top 1,000 LMRs based on PRC2 binding in hESCs are common to the three tissue types and mostly map to developmental genes
- During aging, DNAm generally declines, but high-PRC2 LMRs gain methylation in all of the tissue types
- The effect holds across different methylation datasets analyzed with different methods
The team call this timely approach PRC2-AgeIndex, and it performed comparably to 41 established DNAm clocks. Next, they wanted to see if PRC2-AgeIndex could serve as a biomarker of rejuvenating treatments. Here’s what they found:
- Using mouse genome datasets, they saw that mice on long-term caloric restriction diets have lower PRC2-AgeIndexes compared to old controls
- Mouse skin partially or fully epigenetically reprogrammed via Yamanaka factors—four transcription factors sufficient for inducing pluripotency—have lower PRC2-AgeIndexes compared to controls
As the sands of time ran down, the team also saw that methylation increases in high-PRC2 regions in cancer cells, mitotic cells, and cells that have a high passage number, showing that replication is a strong factor in DNAm gain.
Overall, PRC2-AgeIndex is a robust, unbiased, genome-wide marker of aging and cell passaging based on gain of methylation at regions that likely have biological significance, the team says.
Keep up with your child-like curiosity at Nature Communications, July 2024.