A brain-wide form of presynaptic active zone plasticity orchestrates resilience to brain aging in Drosophila

PLoS Biol. 2022 Dec 5;20(12):e3001730. doi: 10.1371/journal.pbio.3001730. eCollection 2022 Dec.


The brain as a central regulator of stress integration determines what is threatening, stores memories, and regulates physiological adaptations across the aging trajectory. While sleep homeostasis seems to be linked to brain resilience, how age-associated changes intersect to adapt brain resilience to life history remains enigmatic. We here provide evidence that a brain-wide form of presynaptic active zone plasticity ("PreScale"), characterized by increases of active zone scaffold proteins and synaptic vesicle release factors, integrates resilience by coupling sleep, longevity, and memory during early aging of Drosophila. PreScale increased over the brain until mid-age, to then decreased again, and promoted the age-typical adaption of sleep patterns as well as extended longevity, while at the same time it reduced the ability of forming new memories. Genetic induction of PreScale also mimicked early aging-associated adaption of sleep patterns and the neuronal activity/excitability of sleep control neurons. Spermidine supplementation, previously shown to suppress early aging-associated PreScale, also attenuated the age-typical sleep pattern changes. Pharmacological induction of sleep for 2 days in mid-age flies also reset PreScale, restored memory formation, and rejuvenated sleep patterns. Our data suggest that early along the aging trajectory, PreScale acts as an acute, brain-wide form of presynaptic plasticity to steer trade-offs between longevity, sleep, and memory formation in a still plastic phase of early brain aging.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology
  • Animals
  • Brain / physiology
  • Drosophila melanogaster* / genetics
  • Drosophila*
  • Neuronal Plasticity / physiology
  • Synapses / physiology

Grants and funding

This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) to S.J.S. (SFB1315 TP A08, NeuroNex2, CoE NeuroCure and FOR2705 TP05). S.H. was supported by the Chinese Scholarship Council (201504910753) as well as by the Leibniz Association (SAW-2019-ISAS-4-SyMetAge). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.