Aging-related modifications to G protein-coupled receptor signaling diversity

Aging is a highly complex molecular process, affecting nearly all tissue systems in humans and is the highest risk factor in developing neurodegenerative disorders such as Alzheimer's and Parkinson's disease, cardiovascular disease and Type 2 diabetes mellitus. The intense complexity of the aging process creates an incentive to develop more specific drugs that attenuate or even reverse some of the features of premature aging. As our current pharmacopeia is dominated by therapeutics that target members of the G protein-coupled receptor (GPCR) superfamily it may be prudent to search for effective anti-aging therapeutics in this fertile domain. Since the first demonstration of GPCR-based beta-arrestin signaling, it has become clear that an enhanced appreciation of GPCR signaling diversity may facilitate the creation of therapeutics with selective signaling activities. Such 'biased' ligand signaling profiles can be effectively investigated using both standard molecular biological techniques as well as high-dimensionality data analyses. Through a more nuanced appreciation of the quantitative nature across the multiple dimensions of signaling bias that drugs possess, researchers may be able to further refine the efficacy of GPCR modulators to impact the complex aberrations that constitute the aging process. Identifying novel effector profiles could expand the effective pharmacopeia and assist in the design of precision medicines. This review discusses potential non-G protein effectors, and specifically their potential therapeutic suitability in aging and age-related disorders. (c) 2020 Published by Elsevier Inc.

Automated summary

Aging is a complex molecular process that affects almost all tissue systems in humans and is the primary risk factor for neurodegenerative disorders, cardiovascular disease, and Type 2 diabetes. With the current focus on GPCR-targeted therapeutics dominating the pharmacopeia, searching for effective anti-aging treatments in this area may be beneficial. A nuanced understanding of GPCR signaling diversity could lead to the development of therapeutics with selective signaling activities to impact the complex aberrations of the aging process.