The multifaceted role of GLP-1 in metabolic disorders, chronic inflammation, and aging: Mechanisms and therapeutic potential.

Abstract

Glucagon-like peptide-1 (GLP-1), an incretin secreted by intestinal L-cells in response to nutrients, regulates glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and reducing appetite via hypothalamic signaling. Beyond these canonical actions, emerging evidence reveals GLP-1's pleiotropic functions across multiple systems, with relevance to metabolic disorders, chronic inflammation, and aging-related pathologies. This review summarizes molecular mechanisms underlying GLP-1's protective roles, highlighting its contributions to metabolic balance, inhibition of NF-κB-mediated inflammation, and attenuation of cellular aging through mitochondrial enhancement and autophagy promotion. GLP-1 also influences immune cell function and alleviates hallmarks of senescence, thereby offering therapeutic potential beyond diabetes. We further critically assess the translational potential of GLP-1 receptor agonists (GLP-1RAs), pharmacological agents with superior pharmacokinetics versus native GLP-1, in treating conditions linked to dysregulated metabolism, persistent inflammation, and accelerated aging. Despite demonstrated efficacy in preclinical models and clinical studies, important challenges persist, including inter-individual variability, off-target risks, and uncertainties regarding long-term safety. We conclude by emphasizing the necessity of integrated strategies to target the metabolic-inflammatory-aging axis and by advocating optimization of GLP-1RA formulations, identification of predictive biomarkers, and expansion of their utility for age-associated diseases.