Hypothesis

The accumulation of AGE‑crosslinked collagen creates a pathologically stiff extracellular matrix that mechanically reprograms autophagy from a rationing response into a deficient state. We propose that matrix‑derived rigidity activates integrin‑FAK‑SRC signaling, driving nuclear translocation of YAP/TAZ. Nuclear YAP/TAZ directly suppresses the transcription of TFEB and its lysosomal gene network, while simultaneously upregulating TIMP expression, further locking the MMP/TIMP imbalance. Consequently, autophagosome formation proceeds but lysosomal degradation stalls, causing p62 accumulation and defective clearance of glycated proteins. This autophagic bottleneck exacerbates the cellular siege, shifting the balance from controlled cannibalism to energetic collapse.

Testable Predictions

1. In vitro: Human muscle progenitor cells cultured on glycated collagen hydrogels (mimicking AGE crosslinks) will show increased nuclear YAP/TAZ, reduced TFEB mRNA, elevated LC3‑II with concomitant p62 buildup, and impaired autophagic flux measured by bafilomycin A1 chase, compared to cells on non‑glycated collagen of matched stiffness.
2. Pharmacologic rescue: Treating glycated‑collagen cultures with a YAP/TAZ inhibitor (verteporfin) or FAK inhibitor (PF‑573228) will restore TFEB expression, lysosomal acidification (LysoTracker), and autophagic flux without altering matrix stiffness.
3. In vivo: Aged diabetic mice administered verteporfin will exhibit increased autophagic flux in skeletal muscle (LC3‑II/I ratio, reduced p62) despite persistent AGE‑collagen deposition, accompanied by improved myofiber regeneration after injury, whereas MMP‑9 overexpression alone will not rescue flux if YAP/TAZ remains active.
4. Mechanical decoupling: Enzymatic removal of AGE crosslinks using aldehyde‑reactive agents (e.g., alagebrium) will lower matrix stiffness, reduce nuclear YAP/TAZ, and normalize autophagy, confirming that the mechanotransductive signal, not the chemical modification per se, drives the defect.

Falsifiability

If any of the above interventions fail to modify autophagic flux or TFEB activity despite confirmed target engagement, or if autophagic flux improves independently of YAP/TAZ status, the hypothesis would be refuted. Conversely, consistent rescue of autophagy by YAP/TAZ inhibition across mechanical and chemical contexts would support the model.

Broader Implications

Reframing autophagy as a mechanosensitive rationing system links metabolic glycation, ECM remodeling, and nutrient sensing. It suggests that geroprotectors targeting matrix stiffness or YAP/TAZ may re‑engage the cell’s internal siege management without requiring global crosslink breakage, offering a complementary strategy to AGE‑lowering or RAGE blockade.