Disease-associated mutations directionally modulate epigenetic age in iPSC-derived tissues
- 1Center for Regenerative Medicine (CReM) of Boston University, and Boston Medical Center
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.
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BibTeX
@misc{skvir2026diseaseassociated,
title = {{Disease-associated mutations directionally modulate epigenetic age in iPSC-derived tissues}},
author = {N. J. Skvir and T. W. Dowrey and S. F. Cranston and E. MacDonald and R. Giadone and D. Jones and C. S. Golden and B. Pate and M. Labott and M. A. Serrano and K.-D. Alysandratos and K. Vanuytsel and G. J. Murphy},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.30.755445},
url = {https://www.biorxiv.org/content/10.64898/2026.09.30.755445v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Disease-associated mutations directionally modulate epigenetic age in iPSC-derived tissues
AU - N. J. Skvir
AU - T. W. Dowrey
AU - S. F. Cranston
AU - E. MacDonald
AU - R. Giadone
AU - D. Jones
AU - C. S. Golden
AU - B. Pate
AU - M. Labott
AU - M. A. Serrano
AU - K.-D. Alysandratos
AU - K. Vanuytsel
AU - G. J. Murphy
PY - 2026
DA - 2026/09/30
PB - bioRxiv
DO - 10.64898/2026.09.30.755445
UR - https://www.biorxiv.org/content/10.64898/2026.09.30.755445v1
AB - 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.
ER -