Chronic low-grade inflammation drives skeletal aging and neurocognitive decline: inflammaging as a central hub coupling bone-brain aging.

<h4>Background</h4>Global population aging has driven a marked rise in the co-prevalence of osteoporosis and cognitive impairment, and a bidirectional epidemiological association between the two conditions is now supported by multiple meta-analyses. The shared biological mechanisms underlying this comorbidity, however, remain incompletely defined, and the two disorders continue to be managed within largely separate clinical disciplines.<h4>Aim and scope</h4>This review consolidates existing evidence into an integrative immunopathological framework in which inflammaging(definition)-the chronic, low-grade, sterile systemic inflammatory state driven by senescent cells and their senescence(definition)-associated secretory phenotype (SASP)-is examined as a shared upstream driver that concurrently reconfigures skeletal remodeling and central neuroimmune dynamics through the bone-brain axis. We do not claim to identify novel molecular targets; rather, we synthesize an integrative perspective that has been treated in disciplinary silos.<h4>Key mechanistic themes</h4>At the molecular level, persistently elevated SASP-derived cytokines (IL-6, IL-1β, TNF-α) engage RANKL-dependent osteoclastogenesis in bone and prime microglial neuroinflammation in the central nervous system. Chronic NF-κB signaling and NLRP3 inflammasome activation, amplified in preclinical models by mitochondrial DNA release via the cGAS-STING axis, sustain this dual pathological output. Within the bone-brain axis, bone-derived endocrine signaling is remodeled during aging: osteocalcin (OCN) secretion declines, while osteocyte-derived sclerostin (SOST) rises and may antagonize Wnt/β-catenin signaling in both compartments. Blood-brain barrier disruption and peripheral immune-cell infiltration further amplify central neuroinflammation.<h4>Balanced appraisal</h4>We explicitly distinguish (i) conceptual hypotheses, (ii) preclinical (cellular and rodent) findings, and (iii) validated human data. Several widely cited mechanisms-including OCN-GPR158-mediated neuroprotection, cGAS-STING-driven neuroinflammation, and microbiome-based longevity signatures-rest predominantly on murine models or single cohorts and require independent human validation. Microglial responses in the aging brain reflect a heterogeneous state space rather than a uniform pro-inflammatory conversion.<h4>Therapeutic implications</h4>Candidate bone-brain dual-targeting interventions-senolytics(definition) (dasatinib plus quercetin), NLRP3 inhibitors, cGAS-STING blockade, GLP-1 receptor agonists, and microbiota-targeted strategies-are discussed with explicit reference to current evidence level, safety concerns, and translational limitations, rather than as established co-therapies. Dual-endpoint randomized trials enriched for elevated inflammaging biomarkers are needed before any of these agents can be positioned for clinical use in bone-brain comorbidity.<h4>Conclusion</h4>The inflammaging-centered framework advanced here provides a testable integrative pathophysiological perspective on bone-brain aging comorbidity and a rationale for interdisciplinary "bone-brain integrated" clinical evaluation in older adults, which we frame as an aspirational, hypothesis-generating model rather than an evidence-based standard of care.