Failures of DNA Methylation Clocks and Development of a Noise Barometer for Measuring Epigenetic Pressure of Aging and Disease

This study reveals that Elastic Net (EN) DNA methylation clocks are not accurate for predicting individual ages and distinguishing between healthy and diseased cohorts due to the non-linear nature of biological processes. The selection of cytosines for these clocks is not determined by age-related methylation changes, and the selected cytosines vary when non-clock cytosines are removed from the training data. To improve this, the researchers focused on cytosines with stable methylation throughout life, hypothesizing that their dysregulation indicates biological noise, a potential biomarker of aging and disease. They developed a "noise barometer" to measure this noise, finding that about 25% of cytosines in the 450K DNAme array show increased variability with age, supporting the concept of DNA methylation noise as a biomarker for aging and disease.