First-Generation Multi-Tissue Epigenetic Clocks
The next major milestone in the field of epigenetic aging was the
development of multi-tissue epigenetic clocks. Teschendorff et
al. , 201070 described
a set of 69 CpGs with age-associated increases in methylation in both
blood and epithelial tissue, demonstrating a pan-tissue signature of
aging. Koch et al. used Illumina 27K data from four different
tissue types (Table 2 ) to develop a multi-tissue clock with
mean AE of 11 years71.
This clock was quickly followed by two multi-tissue clocks developed by
Horvath et al. : the
pan-tissue53 and Skin
& Blood clocks68.
Since its development, the pan-tissue Horvath
clock53 has been the
backbone of epigenetic aging studies. It was developed using 8,000
samples (from 51 healthy tissues) of Illumina 27K and 450K data, divided
into training and validation cohorts. Elastic net with 10-fold cross
validation was performed on the DNAm values of 21,369 CpG sites with a
log- transformed version of CA as the dependent variable. This
regression yielded a clock of 353 CpG sites with a median AE of 3.6
years in the validation
cohort53. The
pan-tissue Horvath clock has been repeatedly validated and has shown
high accuracy, even when applied to data from the Illumina 850K EPIC
array (missing 19/353 CpG
sites)72, and
robustness to changes in cell type
composition61. However,
the pan-tissue clock underestimates epigenetic age in older
individuals73. In
addition, while this clock is more accurate in pediatric samples than
the Hannum clock61, it
was predominantly developed using adult samples and may not contain the
CpG sites associated with early developmental processes.
The Skin & Blood epigenetic clock is another multi-tissue clock
developed by Horvath et al . It aims to improve the accuracy of
the Horvath pan-tissue clock in
fibroblasts68. The Skin
& Blood clock consists of 391 CpG sites and was developed through a
similar process as the pan-tissue clock, but using Illumina 450K or 850K
array data from buccal cells, fibroblasts, keratinocytes, endothelial
cells, blood, and
saliva68. In addition
to better performance in fibroblasts, this clock is more accurate than
both the Horvath pan-tissue clock and Hannum clock in blood samples
(median AE=2.5 years vs. 3.7 and 5.1
years)68.