Aryl hydrocarbon receptor signaling in osteosarcopenia: an integrative framework for musculoskeletal aging

Aging is accompanied by a progressive decline in tissue integrity and functional capacity and is a major risk factor for chronic disease. Osteosarcopenia, defined as the concurrent loss of bone and skeletal muscle mass and function, is a major contributor to frailty, fractures, disability, and reduced quality of life in older adults. While musculoskeletal aging has traditionally been attributed to endocrine and mechanical factors, growing evidence highlights an important role for environmental, microbial, and dietary signals in influencing tissue homeostasis across the lifespan. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that integrates these diverse cues and has emerged as a critical regulator of musculoskeletal homeostasis. In this review, we examine the emerging role of AhR signaling in the regulation of bone and skeletal muscle biology and discuss how context-dependent AhR signaling contributes to key hallmarks of aging, including oxidative stress, mitochondrial dysfunction, chronic inflammation, altered tryptophan metabolism, and gut dysbiosis. We propose that sustained or dysregulated AhR activation provides a mechanistic link between aging-related systemic stressors and the development of osteosarcopenia, highlighting AhR signaling as a potential target for preserving musculoskeletal health during aging.