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Ageing is associated with genome-wide changes in DNA methylation at CpG sites, which support epigenetic clocks. Reviews have argued that these methylation patterns may reflect regulation at the chromatin level, rather than independent changes at individual CpG sites. ^{[1] [2]}

CRISPR-based epigenetic editing techniques have been used to modify DNA methylation at age-associated CpG sites, including sites near loci used in epigenetic clocks (PDE4C and FHL2). Liesenfelder and others reported that methylation changes at selected loci are followed by modifications at genomically distant CpGs. The authors propose that these modifications may be mediated by chromatin folding that brings distal regulatory regions physically closer.^[3]

CRISPR-based epigenetic editing has been used to alter DNA methylation at selected age-associated CpG sites (including loci in PDE4C and FHL2), reporting methylation changes at many additional, genomically distant CpGs. ^[4] Reviews have mentioned that age-related methylation differences may occur in a coordinated “co-methylation” module, consistent with chromatin-level modifications rather than isolated CpGs. ^{[5] [6]}

In the 2025 study, the authors proposed that distant effects could be influenced by three-dimensional chromatin organization.^[7]

Large epigenome-wide association studies have identified many CpG sites whose DNA methylation levels change with age. Reviews have discussed that age-associated methylation changes often occur in coordinated patterns and are linked to chromatin and genome organization. ^{[8] [9]}

In a 2025 study, CRISPR-based epigenetic editing was implemented to alter methylation at selected age-associated CpG sites (including loci associated with age-related hypermethylation such as PDE4C and FHL2). Authors reported that editing was accompanied by methylation changes at multiple genomically distant CpGs ^[10]

Catalytically inactive versions of CRISPR-Cas9 (dCas) can be linked to effector domains like DNMT3A/3L for gene methylation. ^{[11] [12] [13]}

DNA methylation at CpG sites near PDE4C has been reported to show age-associated changes, and has been used as one of several loci in biological age-prediction models in blood and other tissues ^{[14] [15] [16]}

DNMT3A has been used alongside inactive CRISPR-Cas9 (dCas) constructs for epigenome editing purposes. In this system, guide RNAs direct the dCas9–DNMT3A construct, where it can induce DNA methylation in targeted loci. ^[17]

dCas9–DNMT3A has been used to modify age-associated CpG sites in genes like PDE4C and FHL2, to observe its effects on the epigenetic clock. ^[18]

Catalytically inactive CRISPR Cas9 (dCas9) can be fused with effector domains for epigenome editing at targeted loci. ^{[19] [20]}

In a 2025 study, dCas9–DNMT3A was used to modify age-associated CpG sites in genes like PDE4C and FHL2, to observe its effects on the epigenetic clock. ^[21]

DNA methylation related to aging may be coordinated methylations regulated by the three-dimensional architecture of chromatin. ^{[22] [23] [24]}