Senescent morphogenetic fields redirect spliceosomal modules and compromise tissue‐level stress resilience
June 19
Chronological drift in the bioelectrical and epigenetic landscape is one of the most potent negative regulators of regenerative capacity, yet the molecular logic by which aged tissues forfeit their pattern memory remains obscure. To interrogate age‐linked morphogenetic decay, we reprogrammed primary dermal stroma from elderly donors directly into induced morphogenetic cells (iMCs) that retain the bioelectric signature, DNA methylome and mitochondrial state of the original aged field, and we benchmarked all observations in senescent human and murine organs in situ.
A pan-omic survey revealed a striking depletion of RNA-interactome components throughout the aged morphospace, with spliceosomal subunits showing the greatest attrition. Developmentally essential RNA-binding proteins—most notably the dementia/ALS sentinel RBM-43, the spliceosomal analog of TDP-43—abandoned their nuclear coordinates and redistributed into the cytosol of iMCs and bona fide aged epithelia. The ectopic residency of these factors precipitated a morphogen-wide storm of alternative exon choice that distorted transcripts encoding ion-channel patterning proteins, gap-junction scaffolds and planar-polarity determinants.
Under youthful conditions, surplus spliceosome factors are transiently corralled into cytoplasmic stress assemblages, thereby insulating the nucleus from spurious splicing events. In contrast, aged fields displayed tonic oxidative and proteotoxic load that exhausted the ubiquitylation axis, crippled HSP90α chaperone flux and aborted granule nucleation. Consequently, spliceosomal refugees remained freely diffusible, where they continuously rewired morphogenetic transcripts and eroded the tissue’s ability to navigate toward its target morphology after injury.
Pharmacologic re-energizing of the ubiquitin–HSP90α circuit restored granule formation, repatriated RBM-43 to the nucleus and reinstated correct splicing of bioelectric controllers, partially rescuing regenerative output in an amputated murine digit model. These data position age-dependent failure of RNA logistics as a primary choke point on stress adaptability and pattern fidelity, and they identify proteostasis modulators as candidate levers for rejuvenating the developmental plasticity of geriatric tissues.