Epigenetic Clocks, Resilience, and Multi-Omics Ageing: A Review and the EpiAge-R Conceptual Framework.

Epigenetic clocks have successfully estimated biological age by identifying CpG sites whose DNA methylation levels correlate with chronological age. However, these statistical models provide limited mechanistic insight into the biological underpinnings of ageing. While they capture the "pace" of ageing, they fail to quantify the "resilience" of biological systems-the capacity to recover, reorganize, and maintain homeostasis under stress. To overcome this limitation, we introduce EpiAge-R (Epigenetic Age with Resilience), a mechanistic framework that shifts the focus from passive correlation to active recovery potential. The EpiAge-R framework integrates multilayered biological information-including long-read methylation sequencing, chromatin context, histone modification balance, 3D genome topology, and mitochondrial dynamics-into a unified Resilience Index. By distinguishing between degenerative methylation drift (damage) and adaptive repair processes (resilience), EpiAge-R aligns with nonlinear multi-omics ageing trajectories. This framework provides a quantitative foundation for next-generation biomarkers and precision longevity interventions, aiming to define optimal health rather than statistical normality.