ABL1 tyrosine kinase directly binds mTOR and, in aged mice modeling postoperative cognitive dysfunction (POCD), drives excessive microglial autophagy and neuroinflammation through mTOR/ULK1 signaling. Silencing ABL1 — or blocking autophagy initiation with 3-methyladenine — rescued spatial memory (water maze) and object recognition, reduced hippocampal inflammatory cytokines, and suppressed microglial activation. Mechanistically, ABL1 knockdown paradoxically activated mTOR, which then phosphorylated and inhibited ULK1, braking pathological autophagic flux. Co-immunoprecipitation confirmed physical ABL1–mTOR binding, lending molecular specificity to the pathway.
POCD affects up to 40% of elderly surgical patients and lacks approved pharmacological prevention — making any mechanistic lead clinically meaningful. ABL1 is best known as the oncogenic driver in CML and is already targeted by FDA-approved imatinib-class inhibitors, raising the intriguing possibility of drug repurposing. However, critical caveats apply: this is entirely a mouse study, and translating rodent POCD models to human neurological outcomes has a poor track record. The finding that autophagy suppression is beneficial here also cuts against the prevailing longevity narrative that autophagy induction extends healthspan — context, cell type, and timing clearly matter. The study is mechanistically rigorous but represents an early-stage, incremental advance that requires validation in higher-order models and, ultimately, human trials before any clinical implication can be drawn.
