The GPCR-ome as a central regulator of human healthspan

• Age-related disruption of GPCR networks may connect inflammation, metabolic dysfunction, neurodegeneration, and other hallmarks of aging through shared signaling mechanisms.• Network-level GPCR targeting could move geroscience beyond single-receptor pharmacology toward coordinated, multisystem interventions tailored to aging biology.• AI, multiomics, and digital-twin approaches may enable more precise GPCR-based therapies, but their clinical value will depend on high-quality data, rigorous validation, and overcoming major translational and regulatory barriers.We are living in an era of remarkable global demographic shifts, with most people now expected to live into their seventies and many well beyond. However, this extension of lifespan has also highlighted a persistent gap in "healthspan"-the period of life spent free from chronic, debilitating conditions. Advanced age remains the primary risk factor for a broad spectrum of illnesses, including type 2 diabetes, cardiovascular disease, Alzheimer's disease and other dementias, and cancer. Because the care and treatment of people with these conditions and their comorbidities places an unsustainable strain on healthcare systems, the field of geroscience seeks to target the shared biological root causes of aging itself (1,2).Early therapeutic strategies in this space focused heavily on "senolytics"-compounds engineered to selectively eliminate senescent cells. However, translating senolytic agents from preclinical models to human patients has proven difficult. Because senescent cells share many internal survival pathways with healthy cells in vital tissues, first-generation senolytic approaches have raised concerns about significant systemic adverse effects, including blood disorders or impaired wound healing. These translational hurdles underline the ongoing need for therapeutic strategies with improved tissue selectivity and safety profiles.In their lead article, Boeringer et al. advocate for a systematic focus on the cell surface, specifically targeting G protein-coupled receptors (GPCRs) (1). The largest family of transmembrane proteins in the human genome, GPCRs modulate a wide range of hormonal, metabolic, neural, and immunological processes, many of which tend to undergo dysregulation with age (1,3). Because of their accessibility on the surfaces of virtually every cell, and their vital roles in endocrine, paracrine, and autocrine signaling, GPCRs are already the targets of more than one-third of current pharmacotherapeutics approved by the United States Food and Drug Administration.The authors build their case on a biological convergence across the five major, structurally distinct families: Class A (rhodopsin-like), Class B1 (secretin-like), Class B2 (adhesion), Class C (glutamate), and Class F (Frizzled/Smoothened) (1). Despite their notable structural differences, all five GPCR families show age-related changes in expression, trafficking, or signaling that can disrupt receptor function (1). Human physiological aging is associated with reductions in plasma membrane levels, increased internalization, and reduced heterotrimeric G protein coupling in Class A and Class B1 receptors, as well as defective mechanotransduction and altered dimer stability in Class B2 and Class C families (1). Class F receptors also display an age-related loss of homeostatic tone driven by increased levels of soluble functional antagonists. This convergence of age-related decay of signaling fidelity suggests that aging may act through shared downstream mechanisms, such as molecular chaperone dysfunction, lysosomal decay, and altered lipid raft composition, positioning the GPCR-ome as a deeply interconnected network (1). To understand how this network misfires over time, we must first map the physical and functional architecture that links these families together. Our laboratory has focused on decoding this underlying structural complexity, using multiplexed mapping strategies to systematically chart the functional interactome of GPCRs alongside their critical receptor activity-modifying accessory networks (4). This system-wide interconnectivity underpins Boeringer et al.'s argument that the GPCR-ome behaves as a deeply integrated molecular switchboard (1), providing a rational basis for moving beyond traditional single-receptor pharmacology toward a broader, network-level strategy for rebalancing cellular signaling in aging.One of the most practical applications of this cell-surface framework is the modulation of the cellular secretome, particularly the senescence-associated secretory phenotype (SASP).Senescent cells drive localized tissue damage by developing a SASP and secreting a complex mixture of proinflammatory cytokines, growth factors, and proteases that promote chronic inflammation and drive age-related pathologies across multiple organs (2).The lead article maps how chronic perturbations in specific Class A receptors are linked to systemic and progressive "inflammaging" (1). Specifically, age-associated increases in chemokine receptors, including C-X-C chemokine receptors 2 and 4 (CXCR2/4) and C-C chemokine receptors 2 and 5 (CCR2/5), directly fuel persistent leukocyte activation and chronic inflammation. In this context, the authors highlight the potential of senomorphics to counteract some of these changes using small-molecule therapeutics to modulate or suppress specific hyperactive surface receptors, which in turn may modify or block the production of toxic SASP factors without killing the cell outright (1). Identifying and targeting GPCR pairings that regulate specific proinflammatory interleukins could interrupt the localized inflammatory cascade, thereby protecting surrounding tissues and organs.An important tension in geroscience is the dual role of cellular senescence. Senescence serves as a vital biological defense against oncogenesis, forcing severely damaged or mutated cells into permanent cell-cycle arrest to act as an emergency tum