The triangular drivers of bone aging: mechanistic insights and therapeutic targets in cellular senescence, estrogen deficiency, and gut microenvironment dysregulation

A critical component of organismal aging is skeletal aging, which plays a pivotal role in the onset and progression of various age-related bone disorders and imposes a substantial burden on global public health. Recent studies have increasingly demonstrated that cellular senescence, estrogen deficiency, and gut microenvironment dysregulation serve as core driving forces in skeletal aging. In this review, we introduce the concept of the Skeletal Aging Triangle, aiming to elucidate the intricate interactions among these three factors and their synergistic effects in the skeletal aging process. We provide a comprehensive overview of the mechanisms that trigger cellular senescence within bone tissue, the molecular pathways by which estrogen maintains bone homeostasis, the remote regulation of bone metabolism by the gut microenvironment, and the interconnections among these processes. A deeper understanding of the Skeletal Aging Triangle offers new perspectives for the prevention and treatment of skeletal aging–related diseases, while also contributing to improved patient quality of life and alleviating the healthcare burden on society.