Neural circuits must remain functionally stable while adapting to changing demands and levels of stress. While this balance is thought to rely on plasticity programs integrating molecular and activity-dependent signals, mechanistic models of how such adaptations are orchestrated remain limited. Here, we show that impairment of autophagy in the Drosophila mushroom body (MB) induces brain-wide, post-transcriptional remodeling of presynaptic active zones, characterized by increased expression levels of active zone scaffold proteins, reduced abundance of calcium channel subunits, and elevated levels of Shaker-type potassium channels. This remodeling promotes organismal resilience, as reflected by increased sleep and extended lifespan. Mechanistically, early-life activation of this program is sufficient to extend lifespan, identifying synaptic remodeling as a causal driver of adaptive responses. MB-specific autophagy disruption further leads to non-cell autonomous accumulation of autophagic substrates across the brain, consistent with a system-level proteostatic imbalance in which degradative pathways remain active, but appear insufficient to match cargo load. Our findings identify autophagy in the mushroom body as a key regulator of brain-wide synaptic architecture and resilience, and establish a genetically tractable model for how local proteostatic impairment can trigger adaptive, system-level circuit remodeling.
