The Role of G Protein-Coupled Receptors in Aging and the Modulatory Impact of Physical Activity: A Systematic Review

G protein-coupled receptors (GPCRs), the largest membrane receptor family, are central to regulating physiological processes such as cellular signaling, metabolism, and immunity. Age-related decline in GPCR function causes the systemic inflammation progression, increased oxidative stress, and diminished cellular communication, all of which contribute to the aging pathophysiology. Emerging evidence suggests that exercise may exert beneficial effects by modulating GPCR-related signaling pathways. This systematic review evaluates human interventional studies investigating the physical activity impact on GPCR-associated biological processes in healthy older adults. The review was conducted in accordance with PRISMA guidelines, searching PubMed, Scopus, Web of Science, and SportDiscus databases. Eligible studies included randomized controlled trials (RCTs) and other interventional designs involving participants aged 60 and older, assessing outcomes relevant to GPCR-mediated signaling. Animal model studies, diseased clinical populations, reviews, and meta-analyses were excluded. Out of 913 records screened, 10 met the inclusion criteria. The findings indicate various forms of physical activity reduce GPCR-linked inflammatory biomarkers, enhance mitochondrial antioxidant responses, and favorably modulate metabolic markers. Collectively, the evidence supports physical activity as a non-pharmacological approach to mitigate age-related alterations in GPCR signaling, contributing to healthy aging.