The Intrinsic Epigenetic Aging Clock
One of the noteworthy discoveries of recent years in the ongoing development of aging clocks was that there are sizable differences in epigenetic age when measured between different subtypes of immune cell in a blood sample. This is an important source of measure to measure variability. This has already led some assay providers, such as TruDiagnostic, to implement measures of "intrinsic epigenetic age" that just pick out the more invariant epigenetic marks or cell populations. Here, researchers put forward a modified clock built on the same principles of avoidance, the IntrinClock, that produces the same results from a blood sample regardless of immune cell subtype, and thus doesn't suffer from this problem. It seems plausible that something along these lines will have to be incorporated into present efforts to standardize to one aging clock.
Epigenetic clocks are age predictors that use machine-learning models trained on DNA CpG methylation values to predict chronological or biological age. Increases in predicted epigenetic age relative to chronological age (epigenetic age acceleration) are connected to aging-associated pathologies, and changes in epigenetic age are linked to canonical aging hallmarks. However, epigenetic clocks rely on training data from bulk tissues whose cellular composition changes with age.
Here, we found that human naive CD8+ T cells, which decrease in frequency during aging, exhibit an epigenetic age 15-20 years younger than effector memory CD8+ T cells from the same individual. Importantly, homogenous naive T cells isolated from individuals of different ages show a progressive increase in epigenetic age, indicating that current epigenetic clocks measure two independent variables, aging and immune cell composition. To isolate the age-associated cell intrinsic changes, we created an epigenetic clock, the IntrinClock, that did not change among 10 immune cell types tested. IntrinClock shows a robust predicted epigenetic age increase in a model of replicative senescence in vitro and age reversal during OSKM-mediated reprogramming.