Heterogeneous epigenetic regulatory patterns link mammalian aging, development, and mortality

Aging is often described as a monotonic accumulation of cellular damage, yet all-cause mortality follows a U-shaped trajectory with age, suggesting non-monotonic molecular changes. We investigated links between early childhood development, aging, and chronic diseases by analyzing DNA methylation in mammalian blood. A meta-analysis of 16 human chronic diseases revealed heterogeneous methylation signatures that formed 2 major disease clusters distinguished by their associations with development and sex-related methylation changes. Although epigenetic entropy increased monotonically across the lifespan, several diseases reduced blood DNA methylation entropy independently of blood cell composition. Across mammals, many CpG sites, particularly in intergenic regions, followed U-shaped age-related methylation changes that paralleled mortality curves. Based on these patterns, we developed epigenetic clocks that predict expected mortality across species and tissues and are effective in detecting a range of disease models. Overall, our findings reveal fundamental links between epigenetic regulation during development, aging, and chronic diseases.