Immunosenescence and bone remodeling: from immune cell senescence to skeletal aging through the bone marrow microenvironment

Abstract

With advancing age, the immune system undergoes progressive remodeling termed immunosenescence, which is intimately linked to skeletal homeostasis through the shared bone marrow microenvironment. This review systematically examines how senescent innate and adaptive immune cells disrupt bone remodeling by altering the cytokine milieu and releasing senescence-associated secretory phenotype (SASP) factors. Aged macrophages exhibit enhanced M1 proinflammatory polarization, while neutrophils display increased oxidative burst and delayed apoptosis. Natural killer cells lose cytotoxic capacity, and dendritic cells show impaired antigen presentation yet elevated basal inflammation. Within the adaptive compartment, T helper 17 (Th17) cells expand, regulatory T cells (Tregs) undergo functional decline and lineage instability, and B cells shift from osteoprotegerin (OPG) production toward receptor activator of nuclear factor kappa B ligand (RANKL) expression. These changes collectively elevate the RANKL/OPG ratio, promote osteoclastogenesis, and suppress osteoblast function. Systemic factors including estrogen deficiency and gut dysbiosis further amplify this immune-driven bone loss. Emerging therapeutic strategies range from conventional anti-resorptive agents to senolytics and immune modulators that restore marrow homeostasis. Understanding immunosenescence as an important contributor to skeletal aging provides a conceptual framework for immune-centered prevention and treatment of osteoporosis and fracture complications in the elderly, while recognizing that direct human causal evidence remains limited for several immune cell populations.