Chronological drift of morphogenetic circuits displaces RNA-processing hubs and triggers unrestrained stress signalling in regeneratively exhausted neural tissue
June 19
Chronological decline in the bioelectrical and epigenetic landscape is a central driver of diminished morphogenetic competence, yet the precise cascades by which aged neural collectives forfeit pattern fidelity remain poorly defined. To interrogate these pathways, we executed a direct lineage inflection of dermal fibroblasts obtained from late-life donors into induced proto-neuroepithelial cells, a strategy that conserves the donors’ senescent voltage and chromatin signatures. The converted cells displayed a striking relocalization of spliceosomal scaffold proteins from perinuclear RNA factories to disorganized cytoplasmic granules, coincident with persistent activation of unfolded-protein, oxidative, and integrated stress sensors. Parallel histological and biochemical analyses of geriatric human cortex and senescent murine pallium confirmed identical misplacement of splicing hubs and runaway stress signalling, underscoring a conserved failure of post-transcriptional governance that may underlie age-associated losses in regenerative plasticity.