# Methylation array signals are predictive of chronological age without bisulfite conversion

## TL;DR

This paper shows that DNA methylation data can predict age without bisulfite conversion, but non-methylation factors may interfere with these predictions.

## Contribution

The study identifies pseudomethylation signals as a novel confounding factor in epigenetic clocks and their unique age-predictive properties.

## Key findings

- Non-methylation factors create pseudomethylation signals that affect epigenetic clocks.
- Epigenetic clocks are overrepresented near regions where methylation depends on genetic variants.
- Quantifying these covariates is essential for improving aging studies and epigenetic clocks.

## Abstract

DNA methylation data has been used to make “epigenetic clocks” which attempt to measure chronological and biological aging. These models rely on data derived from bisulfite-based measurements, which exploit a semi-selective deamination and a genomic reference to determine methylation states. We found that non-methylation factors lead to “pseudomethylation” signals that are both confounding of epigenetic clocks and uniquely age predictive. We also failed to predict age using human genotyping arrays, but found that epigenetic clocks were overrepresented near genomic regions whose methylation state is dependent upon sequence variants. Quantifying these covariates in aging studies will be critical to building better clocks and designing appropriate studies of epigenetic aging.

The online version contains supplementary material available at 10.1007/s11357-025-01785-5.