Development of an epigenetic clock resistant to changes in immune cell composition

Area of Science:

• Epigenetics and aging research
• Immunology
• Computational biology

Background:

• Epigenetic clocks predict biological or chronological age using DNA methylation.
• Existing clocks trained on bulk tissues confound aging with cellular composition changes.
• Immune cell populations, like CD8+ T cells, shift with age, impacting bulk tissue methylation.

Purpose of the Study:

• To investigate how changing immune cell composition affects epigenetic age predictions.
• To develop a novel epigenetic clock that measures cell-intrinsic aging.
• To validate the new clock's ability to track aging and age reversal.

Main Methods:

• Analyzed DNA methylation in naive and effector memory CD8+ T cells from individuals of varying ages.
• Developed IntrinClock, an epigenetic clock trained on cell-type-matched samples.
• Tested IntrinClock in vitro using a replicative senescence model and in vivo with OSKM reprogramming.

Main Results:

• Naive CD8+ T cells showed a significantly younger epigenetic age than effector memory cells.
• Homogenous naive T cells demonstrated age-dependent epigenetic age increases, independent of cell composition.
• IntrinClock accurately reflected age progression in senescence and age reversal during reprogramming.

Conclusions:

• Current epigenetic clocks are confounded by age-related shifts in immune cell populations.
• IntrinClock successfully isolates cell-intrinsic aging, providing a more accurate measure of biological age.
• This approach enables precise tracking of aging and interventions like reprogramming for age reversal.