Chronic low-grade inflammation drives skeletal aging and neurocognitive decline: inflammaging as a central hub coupling bone-brain aging
Abstract
Background: 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.
Aim and scope: This review consolidates existing evidence into an integrative immunopathological framework in which inflammaging-the chronic, low-grade, sterile systemic inflammatory state driven by senescent cells and their senescence-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.
Key mechanistic themes: 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…
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