Understanding and making sense of epigenetic age misalignment across different aging clocks

The output of an epigenetic aging clock can vary depending on the training method utilized, cell type composition, the nature of the training dataset, the technology used to generate the methylomic data, acute stressors, and other factors. On an individual level, epigenetic age can fluctuate across different clocks purely due to differences in model training. Among aging clock researchers, it is well-known that the epigenetic age of a single sample can vary across different models. Based on our observations and conversations with longevity scientists and stakeholders, however, this fact is often unappreciated among non-aging clock experts. To help bring more awareness to this important topic, we highlight key literature and, as an illustrative example, use eight blood-trained clocks to show that epigenetic age is frequently misaligned in a publicly available whole blood dataset. Our simple analysis revealed that the average sample difference between the youngest and oldest predicted ages across these clocks was 17 years. The smallest and largest individual-level differences observed were 4 and 45 years, respectively. Clock misalignment has implications for choosing which clock to utilize, interpreting the impact of an intervention on epigenetic age, personalized tracking, and relating epigenetic age to the abstract concept of biological age.