With the new year comes a fresh start, but does the aging epigenome of each one of our cells share this sentiment? To help get your new year off to the right start, a new program known as “scAge” allows the determination of the age of single cells via DNA methylation and reveals insight into how to keep epigenomes forever young.
As reported by Alexandre Trapp, Csaba Kerepesi, and Vadim N. Gladyshev (Harvard Medical School), scAge seeks to overcome problems related to methylation profiling in single cells (such as low and inconsistent CpG coverage) by using a statistical framework based on a probabilistic algorithm to create a single cell “epigenetic clock” that recapitulates chronological tissue aging and describes cell-to-cell heterogeneity.
While we are all still young, we should probably dive straight into the paper from Trapp and colleagues to see all the essential details!
- scAge uses a selection of age-related CpGs and their probabilities to calculate the likelihood that a cell derives from a tissue of a certain age, which avoids the problem associated with the defined CpG sites required for previous epigenetic clocks
- The age of maximum likelihood provides the prediction of epigenetic age
- As proof-of-concept scAge accurately:
- Tracks the aging of single hepatocytes with high resolution and accurately predicts the age of embryonic fibroblasts as close to zero
- Describes the unique nature of epigenetic aging in muscle stem cells, which display minimal epigenetic aging compared to their chronological age
- Tracks the dynamics of aging in embryonic stem cells, which display an epigenetic age close to zero and age in a manner related to the culture conditions employed
- The application of scAge also describes a natural “rejuvenation event” occurring during mid-embryogenesis
- The data provides evidence for the “ground zero” hypothesis of aging by demonstrating a highly significant decrease in the epigenetic age of single cells at gastrulation
Overall, the aggregation of multiple single-cell predictions provides an accurate measure of the age of a particular tissue but also underscores the heterogeneous aging trajectories of individual cells, i.e., all cells age but their single-cell epigenetic clocks tick independently! In the hope of opening new horizons in single-cell epigenetic aging, the team next aims to gain a deeper understanding of how individual CpG methylation events influence each other in single cells and analyze individual aging trajectories of single cells over time and during cell division events.
Furthermore, as if this all wasn’t enough, two related preprints detail how to apply scAge to low-pass bulk bisulfite data and how to integrate this epigenetic tool to create a new method known as tagmentation-based indexing for methylation sequencing (or TIME-Seq).
For more on this fresh start to single-cell epigenetic aging, see Nature Aging, December 2021.