Something thrilling is happening in the fields of epigenetics and aging, where researchers are pulling together old ideas and new experimental results into a paradigm that could offer new explanatory power for why human aging looks the way it does.
As I mentioned in the Sept. 30 newsletter, several researchers are advancing a model of aging that is complementary to the idea that cells simply accumulate damage over time; cells may also lose their specific cell type identities as through the erosion of epigenetic programs dictating that identity.
These observations fit nicely with a decades-old model of how cell identity is established, maintained, and eroded, known as the Waddington landscape, advanced by University of Cambridge biologist Conrad Waddington in the mid-20th century. I had never heard of this idea until recently, which was its own sort of thrill.
My guest this week, Andrew Adey, a researcher at Oregon Health & Science University who studies epigenetics at the single-cell level, helped break the Waddington landscape model down and explain why epigenetic programs, such as methylation, could explain shifts in cell type observed over the human lifespan.
We discussed why methylation is only part of the picture and why combining measurements across modalities (e.g. chromatin accessibility) isn’t always the right call. The right experiment, Adey argues, starts with a clear question rather than the newest technology.
We also delved into our shared love of running and cycling ahead of Adey’s Ironman triathlon this month. Stay tuned to the end for our thoughts on the usefulness of data in training, measuring and estimating power output, and the new paradigm of how to fuel (your brain) for performance.
The episode is also available on Apple Podcasts and Spotify
For more stories, podcasts, and other coverage of genomics, visit www.iongenomics.bio.
Show Notes
Topol Substack Article
“Loss of Cell Identity Drives Human Aging”
Review paper on epigenetics and aging:
Yücel, A.D., Molière, A. & Gladyshev, V.N. “Written in development and lost in ageing: the grammar of cellular identity.” Nature. Sept. 30, 2026. https://doi.org/10.1038/s41586-026-10955-0
Another paper on epigenetics and aging
Lu et al. “Prevalent mesenchymal drift in aging and disease is reversed by partial reprogramming.” Cell. October 2025.
https://www.cell.com/cell/abstract/S0092-8674(25)00853-0
Adey lab preprint on single-cell methylation analysis in the brain:
Rylaarsdam, et al. “Early postnatal DNA methylation dynamics define neuronal subtypes and are disrupted by MECP2 loss.” bioRxiv. June 8, 2026.
https://www.biorxiv.org/content/10.64898/2026.06.06.730504v1
Adey lab Amethyst paper:
Rylaarsdam, et al. “Single-cell DNA methylation analysis tool Amethyst resolves distinct non-CG methylation patterns in human astrocytes and oligodendrocytes.” Commun Biol. Oct. 14, 2025.
Ecker lab paper on non-canonical methylation in the brain:
Lister, et al. “Global epigenomic reconfiguration during mammalian brain development.” Science. July 4, 2013.
https://www.science.org/doi/10.1126/science.1237905
My GenomeWeb story on methylation sequencing tech (paywall):
SciMet v3 paper
Nichols, et al. “Atlas-scale single-cell DNA methylation profiling with sciMETv3.”
Cell Genomics. Jan. 8, 2025.
