Network-level control of G protein-coupled receptors: a panacea for chronic diseases?

G protein-coupled receptors (GPCRs) modulate diverse hormonal, metabolic, neural, and immunological signaling processes. Their age-dependent decline accounts for many fundamental hallmarks of aging, including low-grade inflammation (inflammaging), mitochondrial failure and energy dysregulation, genomic instability and epigenetic dysregulation, dysregulated cellular communication, loss of proteostasis, and cellular senescence. Consequently, GPCR dysfunction underpins nearly all chronic, age-related diseases, including cardiovascular disease, cancer, various endocrine disorders, and neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases. Therefore, the GPCR network (“GPCR-ome”) constitutes a central, druggable, “mega-trophic” regulator of human healthspan. Individual GPCRs present numerous therapeutic targets for specific conditions, many of which are already being exploited, while others show future promise. Alongside this disease-centric approach, the GPCR-ome offers the more radical opportunity to rebalance entire signaling networks to simultaneously correct the multisystem pathological effects of aging itself. Here, we outline a transformative paradigm for network-level, GPCR-based geroprotection that employs artificial intelligence, digital twins, and quantum computational methods to design biased agonists, allosteric or multitarget modulators, heteromer-selective ligands, and polypharmacological strategies to mitigate and manage age-related disorders. We also explore how combinatorial GPCR-based strategies (e.g., coupled with senolytic, metabolic, or regenerative medicines) hold compelling promise to delay multiple hallmarks of aging and enable personalized anti-aging GPCR therapies based on multiomic biomarkers.