Bone Aging and Cellular Senescence Mechanisms

Bone ageing is characterised by a progressive imbalance between new bone formation by osteoblasts and bone resorption by osteoclasts. Skeletal stem and progenitor cells lose proliferative capacity and skew towards adipogenesis, while senescent cells accumulate in the bone microenvironment. These senescent cells secrete pro-inflammatory cytokines, proteases and matrix-modifying factors—collectively termed the senescence-associated secretory phenotype—which further disrupts remodelling. Age-related shifts in immune cell composition, vascular integrity and extracellular matrix stability compound local degenerative processes. Systemic influences such as circadian dysregulation and hormonal decline amplify inflammation and impair bone homeostasis. Given the global burden of age-related osteoporosis, deciphering these interconnected pathways is crucial for developing interventions to preserve skeletal strength, reduce fracture rates and improve quality of life in older populations.

Research from Nature Portfolio

Recent studies have identified a subset of marrow neutrophils that produce elevated transforming growth factor-β1 and drive age-related bone loss. In aged mice and models lacking the intracellular adaptor TRAF3 in mesenchymal progenitor cells, these TGF-β1+CCR5+ neutrophils accumulate via increased CCL5 expression. Pharmacological inhibition of CCR5 restores bone mass in aged animals. Complementary foundational work has shown that TGF-β1 release from resorbing bone induces TRAF3 degradation in mesenchymal progenitors, leading to β-catenin destabilisation, reduced osteoblast formation and enhanced RANKL-mediated osteoclast activation. Stabilising TRAF3 during ageing emerges as a promising strategy to both stimulate bone formation and curb resorption.

Bone Aging and Cellular Senescence Mechanisms publication trend

The graph below shows the total number of articles in bone aging and cellular senescence mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Cellular senescence: A state of irreversible cell cycle arrest accompanied by altered morphology, function and secretory profile.

Senescence-associated secretory phenotype (SASP): A cocktail of pro-inflammatory cytokines, chemokines and proteases secreted by senescent cells that influences neighbouring cells and tissue structure.

Mesenchymal progenitor cell (MPC): A multipotent stromal cell that can differentiate into osteoblasts, adipocytes or chondrocytes and supports bone formation.

Osteoclastogenesis: The differentiation and activation process by which precursor cells become multinucleated, bone-resorbing osteoclasts.

Senolytic: An agent or intervention that selectively induces death of senescent cells to improve tissue function.

References

1. TGFβ1+CCR5+ neutrophil subset increases in bone marrow and causes age-related osteoporosis in male mice. Nature Communications (2023).
2. TGFβ-induced degradation of TRAF3 in mesenchymal progenitor cells causes age-related osteoporosis. Nature Communications (2019).
3. Ageing-related bone and immunity changes: insights into the complex interplay between the skeleton and the immune system. Bone Research (2024).
4. Endothelial BMAL1 decline during aging leads to bone loss by destabilizing extracellular fibrillin-1. Journal of Clinical Investigation (2024).
5. Age‐related increase of CD38 directs osteoclastogenic potential of monocytic myeloid‐derived suppressor cells through mitochondrial dysfunction in male mice. Aging Cell (2024).