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Clinical therapies for age\u2010related musculoskeletal disorders face significant challenges as their pathogenic mechanisms remain largely unclear. This review article focuses on the recent advances in the understanding of regulatory mechanisms of musculoskeletal aging and their clinical relevance. We begin with the prevalence and socioeconomic impacts of major age\u2010related musculoskeletal disorders such as sarcopenia, osteoporosis, osteoarthritis, and degenerative tendinopathy. The current understanding of responsible biological mechanisms involved in general aging is then summarized. Proposed molecular, cellular, and biomechanical mechanisms relevant to the clinical manifestations of aging in the musculoskeletal system are discussed in detail, with a focus on the disorders affecting muscle, bone, articular cartilage, and tendon. Although musculoskeletal aging processes share many common pathways with the aging of other body systems, unique molecular and cellular mechanisms may be involved in the aging processes of musculoskeletal tissues. Advancements in the understanding of regulatory mechanisms of musculoskeletal aging may promote the development of novel treatments for age\u2010related musculoskeletal disorders. Finally, future research directions for major musculoskeletal tissues including functional interaction between the tissues and their clinical relevance to age\u2010related musculoskeletal disorders are highlighted in the Future Prospects section. \u00a9 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. 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