Common Changes in RNA Splicing and Processing with Age Across Tissues

Key Takeaways

• Differential connectivity reveals age‑related genes missed by expression alone
• RNA splicing genes consistently altered across all examined human tissues
• Aberrant splicing correlates with DNA damage response pathways
• Modulating splicing factors extends lifespan in model organisms
• mTOR inhibition may clear defective proteins via enhanced autophagy

Pulse Analysis

The recent study leverages differential connectivity analysis—a network‑centric approach—to capture subtle transcriptional shifts that traditional expression profiling overlooks. By examining a broad age range across diverse human tissues, the authors pinpointed a conserved gene signature dominated by RNA splicing and processing components. This cross‑tissue consistency underscores splicing machinery as a central node in the aging transcriptome, reinforcing earlier observations of widespread intron retention and exon skipping in older cells.

Beyond cataloguing splicing changes, the research draws a mechanistic bridge to DNA damage response pathways, a classic hallmark of aging. Genes involved in DNA repair co‑vary with splicing regulators, suggesting that accumulated genomic lesions may destabilize the spliceosome, leading to aberrant mRNA isoforms. Such dysregulation can cascade into proteostatic stress, impairing organelle function and accelerating cellular senescence. The convergence of splicing errors, DNA damage, and epigenetic drift offers a unified framework for interpreting age‑related molecular decline.

Importantly, the study aligns with experimental evidence that modulating specific splicing factors prolongs lifespan in worms, flies, and mice, and that longevity‑promoting interventions—dietary restriction and mTOR inhibition—normalize splicing patterns. By enhancing autophagic clearance of malformed proteins, mTOR inhibitors may indirectly support spliceosomal fidelity. These insights position RNA splicing not only as a biomarker of biological age but also as a viable target for therapeutics aimed at extending healthspan.