Disease-associated mutations directionally modulate epigenetic age in iPSC-derived tissues

Authors

Skvir, N. J., Dowrey, T. W., Cranston, S. F., MacDonald, E., Giadone, R., Jones, D., Golden, C. S., Pate, B., Labott, M., Serrano, M. A., Alysandratos, K.-D., Vanuytsel, K., Murphy, G. J.

Abstract

Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) resets epigenetic age, creating a major challenge for modeling age-associated cellular states and limiting the use of iPSCs in aging research beyond the genetic component. Recent work has shown that healthy organoids can re-accumulate age-associated epigenetic states over extended culture; whether disease-associated genetic states can directionally reshape these trajectories after reprogramming remains unknown. Here, we present a reproducible, in-vitro approach to re-establish epigenetic aging trajectories using iPSC-derived organoid systems, as quantified by multiple epigenetic clock models. We first demonstrate that epigenetic age progressively increases with serial passaging in a lung organoid model (alveolospheres). We then show that disease-associated mutations in multiple models drive additional, cell-intrinsic shifts in epigenetic age, implicating disease state as an independent modulator of epigenetic clocks. Together, these findings reinforce that iPSC-derived organoids recapitulate epigenetic aging trajectories over time, while highlighting disease state as a potent and potentially tractable modulator of epigenetic age in vitro. By enabling more faithful modeling of age-associated cellular states, this approach expands the utility of iPSC-based systems for dissecting the molecular mechanisms that regulate human aging.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 06 Oct 2026.

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