Inflammaging-Driven PRMT5 Sequestration Creates a Splicing Commitment Point for Irreversible Senescence Reversible by Caloric Restriction Mimetics

Background: Age-associated decline in splicing regulatory factors (SRSF1, HNRNPK, PRMT5) correlates with cellular senescence and inflammaging. PRMT5 symmetrically dimethylates Sm proteins essential for spliceosome assembly. Meanwhile, NF-κB hyperactivation during inflammaging diverts PRMT5 toward inflammatory gene promoters.

Hypothesis: Chronic inflammaging creates a competitive substrate trap where NF-κB–driven transcription sequesters PRMT5 from spliceosome biogenesis, causing progressive accumulation of mis-spliced p16^INK4a and p53 isoforms that bypass normal cell-cycle checkpoints and commit cells to irreversible senescence. This defines a quantifiable splicing commitment point (SCP) — a threshold ratio of canonical-to-aberrant p16/p53 splice variants below which senescence becomes refractory to senolytic clearance. Caloric restriction mimetics (metformin, rapamycin) restore PRMT5 spliceosomal availability by dampening NF-κB, thereby raising the SCP threshold and maintaining senolytic sensitivity.

Testable Predictions:

1. PRMT5 ChIP-seq in aged vs. young fibroblasts will show redistribution from snRNP gene loci to NF-κB target promoters, quantifiable as a PRMT5 Spliceosomal Occupancy Index (PSOI).
2. Single-cell long-read RNA-seq will identify a p16/p53 splice variant ratio threshold below which navitoclax/dasatinib+quercetin fail to induce apoptosis in senescent cells.
3. Pre-treatment with rapamycin (2 weeks) in aged mice will restore PSOI, normalize p16/p53 splicing ratios, and rescue senolytic efficacy by >40% as measured by SA-β-gal clearance and GrimAge deceleration.
4. In rheumatoid arthritis synovial fibroblasts (which exhibit both inflammaging and premature senescence), PRMT5 inhibition will phenocopy accelerated epigenetic aging (DunedinPACE), while PRMT5 overexpression will reverse it.

Significance: This model explains why senolytics show variable efficacy in aged organisms — cells past the SCP are splicing-committed to senescence and resistant to apoptotic priming. Combining CRMs with senolytics in a sequential protocol (CRM priming → senolytic) could dramatically improve healthspan interventions. The PSOI could serve as a novel biomarker for senolytic treatment timing.