Senescent cells act as metabolic hubs that support autophagy in neighboring cells through SASP-mediated AMPK activation. When AMPK is active in senescent cells it phosphorylates ULK1 and inhibits mTORC1, a shift that promotes autophagosome formation while simultaneously dampening NF‑κB‑driven SASP[5][4]. This creates a feedback loop where senescent cells limit their own inflammatory output while releasing soluble factors—such as AMP, ADP, or exosomes containing phosphorylated ULK1—that activate AMPK in adjacent stromal and stem cells. Consequently, the local tissue experiences elevated autophagy flux, which clears damaged mitochondria and limits oxidative stress, thereby preserving tissue function and restraining aberrant proliferation.

We hypothesize that broad‑spectrum senolytics disrupt this AMPK‑dependent paracrine autophagy network, leading to a transient deficit in autophagic capacity in the senescent cell microenvironment. This deficit would manifest as reduced LC3‑II conversion and increased p62 accumulation in neighboring cells, followed by mitochondrial dysfunction and a secondary wave of stress‑induced senescence that could offset the initial benefits of senescent‑cell clearance.

To test this, we propose three complementary experiments: (1) Treat young and aged murine tissues with a senolytic cocktail (e.g., dasatinib + quercetin) and measure AMPK‑pULK1 levels and autophagic flux (LC3‑II/I ratio, p62 turnover) in CD45‑negative stromal cells isolated 24 h post‑treatment[2]; (2) Co‑culture senescent fibroblasts (induced by irradiation) with naive epithelial cells, then add AMPK inhibitor (Compound C) or ULK1 siRNA to the senescent layer and assess whether autophagy markers in the epithelial compartment decline; (3) Rescue experiments where purified SASP‑enriched exosomes from AMPK‑active senescent cells are added to senolytic‑treated cultures, predicting restoration of LC3‑II lipidation and mitigation of ROS‑induced DNA damage.

If the hypothesis holds, senolytic efficacy will be context‑dependent: tissues that rely heavily on senescent‑cell‑driven AMPK signaling (e.g., muscle satellite‑cell niches) will show impaired regeneration after clearance, whereas tissues where senescent cells are predominantly pro‑fibrotic (p21^high SASP) will benefit. This reframes senolytics not as universally beneficial agents but as tools whose outcomes hinge on the metabolic dialogue senescent cells maintain with their neighbors.