Comparative single-cell multiomic analysis reveals evolutionarily conserved and species-specific cellular mechanisms mediating natural retinal aging [Zebrafish multiome_ATAC]

To systematically characterize molecular mechanisms underlying retinal aging, we performed integrated single- cell RNA- and ATAC-Seq analyses of the retina and retinal pigment epithelium (RPE) across the natural lifespan in zebrafish, mice, and humans. By profiling gene expression and chromatin accessibility, we identified extensive cell type- and species-specific aging-dependent changes, with a much smaller number of broadly expressed and conserved genes that include regulators of inflammation and autophagy.

We constructed predictive aging clocks for retinal cell types and observed dynamic, reversible shifts in cellular age following acute injury. Spatial transcriptomic analysis revealed region-specific aging signatures and proximity effects, with Müller glia exhibiting pro-rejuvenating influences on neighboring neurons. Targeted Müller glia-specific induction of Yamanaka factors reduced molecular age in rod photoreceptors and bipolar cells without altering glial age.