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bioRxiv · 10.1101/2025.09.18.677241

REVIVE-Flow: A Foundation Model for Blood DNAm Aging

Litman, E.·Myers, T.·Agarwal, V.·Mittal, E.·Gopinath, A.·Kassis, T.
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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 ODEs 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 {approx} 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.

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Litman, E., Myers, T., Agarwal, V., Mittal, E., Gopinath, A., Kassis, T.. 2025-09-21. REVIVE-Flow: A Foundation Model for Blood DNAm Aging. https://doi.org/10.1101/2025.09.18.677241

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