The Senescent Macrophage as a Central Hub in Skeletal Aging: Mechanisms, Niche Disruption, and Systemic Consequences

Bone marrow macrophages (BMMs) coordinate skeletal remodelling, haematopoietic niche function, immune surveillance, and tissue repair. Whether a persistent senescent state in BMMs is a causal driver of skeletal ageing, however, remains unresolved. The central challenge is both definitional and causal: macrophages may be quiescent, terminally differentiated, chronically activated, tolerant, or metabolically dysfunctional, whereas commonly used senescence markers-including p16^INK4a, p21^CIP1, senescence-associated β-galactosidase activity, and individual senescence-associated secretory phenotype factors-lack diagnostic specificity when used in isolation. In this critical Review, we distinguish evidence for senescence in anatomically defined BMMs from observations in aged marrow myeloid cells, broad myeloid perturbations, systemic senolysis, and mechanistic extrapolation from other tissues. We organize the evidence using a five-link causal chain connecting BMM identity and ontogeny, multidimensional validation of senescence, a defined macrophage-derived mediator, a response in an identified recipient cell, and phenotypic rescue after BMM-specific intervention. Current evidence supports age-associated macrophage-state changes that influence osteoblast support, bone repair, haematopoietic regulation, and inflammatory signalling. It does not yet establish that rigorously defined senescent resident BMMs are necessary or sufficient for age-related bone loss. Evidence for BMM-specific control of vascular dysfunction, haematopoietic bias, and distant-organ ageing is weaker still. The most defensible current model is therefore that senescent or persistently dysfunctional BMMs act as context-dependent amplifiers within an ageing marrow network rather than as universally established initiators. Resolving this question will require spatially resolved state validation, intersectional lineage targeting, temporally controlled necessity and sufficiency experiments, mediator-specific rescue, and validation in human bone marrow.