Chronic Inflammation in the Aging of Bone and Brain Tissue
Researchers here discuss the chronic inflammation of aging as a contribution to the bidirectional relationship between the loss of bone mineral density leading to osteoporosis and neurodegenerative pathology leading to cognitive impairment. As they point out, the best interpretation of the correlation between these two aspects of aging is that underlying processes contribute to both forms of degenerative aging. The chronic inflammatory signaling characteristic of aging is one of the best candidate mechanisms, given what is known of its effects on bone tissue and brain tissue at the detail level.
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. Meta-analytical evidence indicates that osteoporosis is associated with a substantially elevated risk of cognitive impairment (odds ratio = 2.01), and that cognitive impairment carries a reciprocally increased risk of osteoporosis (risk ratio = 1.56) - with Alzheimer's disease conferring a particularly high risk (risk ratio = 1.70). This bidirectional association is best interpreted as the shared output of multiple interlocking aging mechanisms rather than as a direct causal relationship between the two conditions.
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.
Candidate bone-brain dual-targeting interventions - senolytics (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.