Inflammaging fibroblast senescence drives extracellular matrix collapse and satellite cell dysfunction in presbyphonia

Hypothesis

Aging vocal folds develop a pro‑inflammatory fibroblast phenotype that secretes matrix metalloproteinase‑9 (MMP‑9) and interleukin‑6 (IL‑6), leading to lamina propria extracellular matrix (ECM) degradation. The same fibroblast senescence‑associated secretory phenotype (SASP) creates a paracrine niche that suppresses thyroarytenoid satellite cell proliferation despite intact activation, via elevated TGF‑β1 and exosomal miR‑21. Consequently, ECM thinning and muscle atrophy are mechanistically coupled rather than independent processes in presbyphonia.

Mechanistic Basis

Recent data show that presbyphonia affects ~17.78 % of older adults with dysphonia and that lamina propria ECM remodeling is poorly quantified【https://pubs.asha.org/doi/10.1044/2023_AJSLP-23-00143】. Animal thyroarytenoid studies reveal a regeneration index of 0.57 in aged rats, indicating reduced satellite cell mitotic activity despite preserved activation【https://pmc.ncbi.nlm.nih.gov/articles/PMC3522788】. Multi‑tissue mouse aging atlases demonstrate widespread epigenomic inflammation (“inflammaging”)【https://doi.org/10.1101/gr.240093.118】, and single‑cell atlases of laryngeal disease have proven feasible【https://pmc.ncbi.nlm.nih.gov/articles/PMC12314508】. These observations suggest that inflammatory fibroblasts in the lamina propria could be the missing link between ECM loss and satellite cell dysfunction.

Predictions & Experimental Design

1. Spatial transcriptomics of aged human vocal fold biopsies will reveal co‑localization of fibroblast senescence markers (CDKN2A/p16INK4a, IL6, MMP9) with zones of depleted collagen I/III and elastin transcripts.
2. The same regions will show reduced expression of satellite cell activation markers (PAX7, MYOD1) and proliferation Ki‑67, despite normal levels of early activation markers such as CXCR4.
3. Proteomic analysis will detect elevated MMP‑9 activity and increased TGF‑β1 ligand concentration in the lamina propria of presophonic samples versus age‑matched controls.
4. In‑vitro co‑culture of primary lamina propria fibroblasts from old donors with thyroarytenoid satellite cells will recapitulate the proliferation defect; neutralizing IL‑6 or blocking TGF‑β1 signaling will rescue satellite cell entry into S‑phase.
5. Exosome‑sequencing will identify enrichment of miR‑21 in fibroblast‑derived vesicles, and transfection of satellite cells with miR‑21 mimic will suppress MyoD translation, whereas antagomiR‑21 will restore it.

Falsifiability: If spatial maps show no overlap between fibroblast SASP signatures and ECM degradation zones, or if satellite cell proliferation remains unchanged after IL‑6/TGF‑β1 blockade, the hypothesis is refuted.

Potential Implications

Establishing a fibroblast‑centric mechanism would justify targeting senescent fibroblasts (e.g., with senolytics or JAK/STAT inhibitors) to preserve lamina propria integrity and improve satellite cell‑mediated muscle repair, offering a disease‑modifying strategy for presbyphonia that goes beyond symptomatic voice therapy.