Considering Shifts in Cell Types in Bulk Tissue Samples Assessed for Epigenetic Age
Epigenetic clocks assess data derived from a bulk set of cells derived from tissues. This will be a mix of cells of different types and subpopulations, and thus some portion of age-related changes might be due to shifts in the relative numbers of these cell types. This has already been explored to some degree in the context of white blood cells in a blood sample, and the better commercial epigenetic age assays are now somewhat improved for that exploration. Here researchers discuss the problem more generally, and demonstrate that separating out cell types can be expected to improve epigenetic clocks and age assessment for any tissue.
The ability to accurately quantify biological age could help monitor and control healthy aging. Epigenetic clocks have emerged as promising tools for estimating biological age, yet they have been developed from heterogeneous bulk tissues, and are thus composites of two aging processes, one reflecting the change of cell-type composition with age and another reflecting the aging of individual cell-types. There is thus a need to dissect and quantify these two components of epigenetic clocks, and to develop epigenetic clocks that can yield biological age estimates at cell-type resolution.
Here we demonstrate that in blood and brain, approximately 39% and 12% of an epigenetic clock's accuracy is driven by underlying shifts in lymphocyte and neuronal subsets, respectively. Using brain and liver tissue as prototypes, we build and validate neuron and hepatocyte specific DNA methylation clocks, and demonstrate that these cell-type specific clocks yield improved estimates of chronological age in the corresponding cell and tissue-types. We find that neuron and glia specific clocks display biological age acceleration in Alzheimer's disease with the effect being strongest for glia in the temporal lobe. Moreover, CpGs from these clocks display a small but significant overlap with the causal DamAge clock, mapping to key genes implicated in neurodegeneration. The hepatocyte clock is found accelerated in liver under various pathological conditions. In contrast, non-cell-type specific clocks do not display biological age-acceleration, or only do so marginally.