Paper: Epigenetic editing at individual age-associated CpGs affects the genome-wide epigenetic aging landscape.

Authors: Liesenfelder, S., Elsafi Mabrouk, M.H., Iliescu, J. *et al.*. The corresponding author is Wolfgang Wagner.

Journal: Nature Aging

Published: 24 March 2025.

DOI: https://doi.org/10.1038/s43587-025-00841-1 (This DOI can be used to access the paper.)

This week, we delve into a fascinating paper from Nature Aging that explores the impact of **epigenetic editing at individual age-associated CpG sites on the broader epigenetic aging landscape**. Researchers, including S. Liesenfelder and Wolfgang Wagner, utilized CRISPR-based editing tools (dCas9-DNMT3A, CRISPRoff) to target specific CpG sites and observed **genome-wide methylation changes, termed "bystander effects"**. These effects were found to be **reproducible and linked to 3D chromatin interactions**. Notably, **hypermethylation at age-associated sites showed greater stability compared to hypomethylated targets**.

This paper raises some critical questions for the longevity biotech field:

As one talking point suggests, **"If aging is an orchestra, this paper shows the musicians talk to each other—but we still don’t know who’s the conductor"**. How do these localized epigenetic edits propagate and influence the wider genome?

Another point to consider: **"Editing one CpG is like poking a spiderweb: the whole structure vibrates, but does it matter for the spider?"**. Are these genome-wide changes functionally significant for the aging process?

The study uses **epigenetic clocks**, which are highlighted as **"like a car’s dashboard warning lights. Fixing the light doesn’t fix the engine"**. Does altering these clocks through epigenetic editing truly impact the underlying mechanisms of aging, or are we just tweaking a biomarker?

While the paper demonstrates these bystander effects, it's important to consider the magnitude of the changes, with opinions noting that the hyper-CpG changes in Fig 5ab may not be that impressive.

The relevance of epigenetic clocks for interventions also needs scrutiny, as they are not yet fully validated for this purpose.

There's potential for applying information theory and compression concepts to better understand the communication within this epigenetic network.

We will discuss the potential implications of these "bystander effects" and consider the limitations of using epigenetic clocks as direct targets for anti-aging therapies, especially in the absence of more supporting research. We will also briefly touch on related research in epigenetic editing and its broader applications.