How epigenetic clocks tick: unpacking the black box by deciphering biological pathways and transcriptomic signatures of accelerated aging

Thalida Em Arpawong, Steve Cole, Harshanna Badhesha, Jung Ki Kim, Christopher R. Beam, Eric T. Klopack, Kimberly Siegmund, Bharat Thyagarajan, Eileen M. Crimmins

1. 01

   n = 3,227 HRS participants with paired DNA methylation and RNA-sequencing

2. 02

   The five canonical clocks showed more unique than shared enriched biological pathways

3. 03

   Clock-specific signatures spanned immune activity, metabolism, cell growth and signalling

4. 04

   Derived transcriptomic aging gene scores (TAGS) sometimes outperformed the DNAm clocks for morbidity and mortality association

5. 05

   Implies a single reported "biological age" number conceals which clock, and therefore which biology, produced it

Study Design

Cohort Study

Sample Size

3,227 subjects

Study Duration

Not reported

Methodology

Cross-sectional differential gene expression analysis against epigenetic age acceleration in a nationally representative US cohort with contemporaneous DNAm and RNA-seq, followed by derivation and phenotype-association testing of transcriptomic aging gene scores.

Limitations

Cross-sectional design; blood tissue only, so tissue-specific aging is not captured. Published as an unedited accepted manuscript pending final editing. TAGS are newly derived and await external validation.