As for all tissues, bone derives its structural properties from the composition and structure of its extracellular matrix. This matrix constantly undergoes dynamic modification: osteoclast cells break down the matrix, while osteoblast cells build it up. Throughout much of adult life, a sufficient balance exists between these processes of creation and destruction to ensure that bones remain structurally sound. With old age, however, the balance shifts slowly to favor osteoclasts. The result is a loss of bone mineral density over time, leading eventually to osteoporosis, brittle bones, and fracture or breakage in an already frail elderly individual.
The aging of the immune system is one of the contributing factors to this erosion of bone tissue maintenance. Chronic inflammation on the part of the immune system is a feature of aging, driven by maladaptive reactions to damage and dysfunction, and this is disruptive to the balance between osteoblasts and osteoclasts. There are other issues besides this. For example, innate immune cells are deeply involved in tissue maintenance, but too many of these cells relinquish these necessary tasks to adopt other, less helpful behaviors in aged tissues. Today’s open access paper reviews the aging of the immune system through the lens of bone tissue, the links between what is known of immune aging and what is known of the declining maintenance of bones.
Immune cell senescence is an important intermediary linking organismal ageing, chronic low-grade inflammation, and disordered bone metabolism. With advancing age, immune cells undergo systemic functional remodeling and exhibit a series of characteristic alterations, including reduced proliferative capacity, skewed differentiation, abnormal migration and homing, impaired phagocytic and clearance functions, and changes in their secretory profile. These changes persistently disrupt the osteoimmune microenvironment and ultimately promote enhanced bone resorption, suppressed bone formation, and deterioration of bone quality.
This review centers on the immunological basis of bone homeostasis and systematically summarizes the major biological features of immune cell senescence, with a particular focus on the key cellular mechanisms through which it drives chronic bone disease. It further analyses its pathological manifestations and disease-specific differences in osteoporosis, osteoarthritis, rheumatoid arthritis, and diabetes-related bone disease. Current evidence indicates that the contribution of immune cell senescence varies across different diseases: its pathogenic association appears to be relatively more direct in osteoporosis and rheumatoid arthritis, whereas in osteoarthritis and diabetes-related bone disease it more often acts as a contributor to inflammatory amplification and microenvironmental deterioration.
At present, intervention strategies targeting immune cell senescence mainly focus on modulation of macrophage polarization, immune-mediated clearance of senescent cells, restoration of adaptive immune homeostasis, and mesenchymal stem cell (MSC)-related improvement of the local microenvironment, but overall these approaches remain at the preclinical or early translational stage. Future studies should integrate single-cell sequencing, spatial transcriptomics, and multi-omics approaches to define local immune cell senescence landscapes and establish robust biomarker systems, thereby promoting the transition from mechanistic research to precision intervention in chronic bone diseases.
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