SASP‑Driven Rewiring of Autophagic Cargo Hierarchy Drives Age‑Related Tissue Decline

The seed idea frames autophagy as a ordered cannibalism ritual rather than indiscriminate housekeeping. Building on this, we hypothesize that soluble senescence‑associated secretory phenotype (SASP) factors remodel the selective autophagy cargo receptor hierarchy in neighboring cells, causing a maladaptive shift in organelle turnover that underlies age‑related functional decline. Specifically, we propose that IL‑6 and IL‑8, acting through JAK/STAT3 and NF‑κB signaling, transcriptionally upregulate p62/SQSTM1 while suppressing NBR1 and OPTN expression in a distance‑dependent gradient emanating from senescent fibroblasts. This receptor bias redirects autophagic flux toward ubiquitin‑tagged protein aggregates and away from mitochondria and peroxisomes, leading to progressive accumulation of damaged organelles despite overall autophagy activity remaining intact.

Mechanistically, the shift occurs because p62 favors ubiquitinated cytosolic proteins, whereas NBR1 and OPTN are more efficient at recruiting depolarized mitochondria (via LC3 interaction regions) and peroxisomal proteins. SASP‑induced STAT3 phosphorylation increases p62 promoter activity, while NF‑κB‑dependent transcriptional repressors decrease NBR1/OPTN transcription. The resulting cargo receptor imbalance creates a "triage" where the cell prioritizes protein clearance over organelle renewal, a trade‑off that is beneficial during acute stress but detrimental when sustained, causing mitochondrial dysfunction, ROS elevation, and impaired tissue regeneration.

Testable predictions: (1) In aged mouse muscle, spatial transcriptomics will reveal a radial decrease in NBR1 and OPTN mRNA and a concomitant increase in p62/SQSTM1 expression with proximity to senescent cells identified by p16^INK4a^ or SASP staining. (2) Exogenous IL‑6 or IL‑8 treatment of young myotubes will recapitulate this receptor gradient in vitro, measurable by quantitative immunofluorescence and RNA‑FISH at single‑cell resolution. (3) Genetic knockdown of p62 or overexpression of NBR1 in fibroblasts adjacent to senescent cells will rescue mitochondrial membrane potential and reduce ROS, improving muscle fiber hypertrophy in vivo. (4) Pharmacologic inhibition of JAK/STAT3 will flatten the autophagy receptor gradient and restore balanced mitophagy without altering overall LC3‑II turnover.

Falsification would occur if spatial mapping shows no distance‑dependent alteration in autophagy receptor expression, or if manipulating IL‑6/IL‑8 signaling fails to shift cargo preference despite changes in SASP levels. Conversely, confirmation would support the notion that age‑related decline stems not from autophagic insufficiency but from a SASP‑driven rewiring of the autophagy hierarchy, offering a precise target for interventions that restore organelle quality control.