Second-Generation Epigenetic Clocks
First-generation epigenetic clocks are useful in the study of phenotypes
and healthy aging, but may not select health informative CpG sites
because they were trained exclusively on CA (rather than variables more
tightly linked to health
status12.
Second-generation epigenetic clocks are trained on proxy variables
(e.g., five plasma proteins, and smoking status) for biological aging in
addition to CA. These clocks aim to improve on the performance of the
first-generation clocks in predicting disease development and mortality.
PhenoAge66 and
GrimAge76(Table 3 ) are second-generation clocks and predict mortality
more accurately than first generation clocks. However, there are several
key limitations. The clinical markers used to generate a composite
“biological age” value makes these clocks difficult to implement in
many contexts, as such detailed health data may not always be available.
Clinical variables used in the development of these clocks may be
relevant to aging in older adults but may not be informative of
biological aging in pediatric samples. Pediatric-specific
second-generation clocks may be needed to assess the accuracy of
second-generation clocks in predicting childhood phenotypes.