The functional integrity of the proteome is governed by the dynamic architecture of the Proteostasis Network (PN), which integrates protein synthesis, folding, trafficking, and degradation to maintain cellular and organismal resilience.

In metazoans, proteostasis is coordinated systemically through cell-nonautonomous communication. Sensory neurons, for instance, utilize neuropeptide signaling to regulate the organismal heat shock response and synchronize tissue-level defenses against misfolded, aggregation-prone proteins.

During aging, proteostasis collapse is programmed by germline-to-soma signaling, where the epigenetic deposition of repressive chromatin at heat shock gene loci suppresses stress-responsive transcriptional programs. This age-dependent proteostasis collapse triggers widespread conformational shifts across nearly one-third of the proteome, affecting protein solubility, aggregation, and protein abundance throughout all tissues.

These structural alterations are not unique to physiological aging and are observed in disease models expressing temperature-sensitive proteins or expanded polyglutamine tracts.