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

Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) has the ability to reset epigenetic age, presenting a challenge for modeling age-related cellular states and limiting the use of iPSCs in aging research beyond the genetic aspect. Research has shown that healthy organoids can re-accumulate age-related epigenetic states over long cultures; however, whether disease-associated genetic states can influence these trajectories after reprogramming remains unclear.

In this study, a reproducible in-vitro method to restore epigenetic aging trajectories using iPSC-derived organoid systems is presented, as measured by various epigenetic clock models. The researchers first prove that epigenetic age steadily rises with successive passaging in a lung organoid model (alveolospheres). They then reveal that disease-associated mutations in various models induce further, intrinsic changes in epigenetic age, suggesting that disease state acts as an independent factor in modulating epigenetic clocks.

These findings confirm that iPSC-derived organoids accurately mimic epigenetic aging trajectories over time, while also emphasizing disease state as a powerful and potentially easy-to-manipulate determinant of epigenetic age in a laboratory setting. This method enhances the reliability of modeling age-related cellular states, thereby expanding the applicability of iPSC-based systems in exploring the molecular mechanisms that govern human aging.