REVIVE-Flow: A Foundation Model for Blood DNAm Aging

Abstract

Epigenetic clocks can predict biological age but cannot prescribe the interventions needed to reverse it. Here, we introduce REjuVenatIon Via Epigenetic Flow (REVIVE-Flow), a flow-matching model trained on a broad compendium of epigenetic blood studies to transport methylomes forward and backward in time. First, we learn the continuous vector field of aging as an Ordinary Differential Equation (ODE) within a stable, low-dimensional linear space. Then, the learned ODE\'s dynamics are integrated backward in time to define a natural, biologically-plausible rejuvenation trajectory. This path serves as a guide for a convex optimization problem that identifies the minimal, targeted CpG-level perturbation required to rejuvenate a sample. On a completely unseen test set comprising over 800 individuals from the European Prospective Investigation into Cancer and Nutrition (EPIC-Italy) cohort, Revive achieves 0.4 years rejuvenated per commanded year (R2=0.99), with a smooth sparsity-effect trade-off. Extensive validation confirms the effect preserves inferred cell-type composition and targets biologically plausible loci enriched in genomic regions and pathways central to aging biology.