GPCR systems coordinate cellular resilience against aging-associated stress.

Aging-related diseases arise from cumulative cellular damage driven by diverse stressors. G protein-coupled receptors (GPCRs) play a critical role in coordinating cellular resilience to these stressors. We propose that stable multiprotein GPCR complexes-termed "receptorsomes"-function as adaptive hubs that sense, integrate, and mitigate stress across subcellular compartments. Receptorsomes comprise a GPCR core non-covalently associated with specific adaptors (e.g., β-arrestins, GIT2, RGS proteins, ASK1, YAP/TAZ), enabling pluridimensional, G protein-independent signaling that balances stress detection, damage repair, and homeostasis. This review synthesizes evidence linking receptosome composition to responses against oxidative, proteostatic, hypoxic, and other stressors, mapping these to aging hallmarks. We hypothesize that therapeutically tuning receptorsome adaptor engagement could enhance resilience, delay pathology, and extend health span, offering predictions for future testing.