Fracture Healing Mechanisms in Aging Models

Fracture healing proceeds through sequential inflammatory, reparative and remodelling phases that culminate in restoration of bone integrity. Ageing profoundly alters each phase, leading to delayed callus formation, impaired angiogenesis and dysregulated bone turnover. Early inflammation in aged organisms is marked by prolonged recruitment of pro-inflammatory macrophage subsets and elevated cytokine production, a phenomenon often termed inflammaging. This persistent inflammatory milieu impairs mesenchymal stem cell differentiation into osteoblasts and slows endochondral ossification. Concurrently, diminished neovascularisation within the callus restricts nutrient delivery and osteoprogenitor migration. In later stages, an imbalance between osteoblast-mediated bone formation and osteoclast-mediated resorption results in weakened remodelling capacity, increasing the risk of non-union. Molecular pathways implicated in ageing fracture repair include altered Wnt/β-catenin signalling, impaired expression of angiogenic regulators such as VEGF and dysregulated immune mediators including interleukin-22 and TREM2. Preclinical ageing models have highlighted the pivotal role of systemic factors and local cell populations in maintaining the delicate coordination of inflammation, angiogenesis and ossification. A deeper mechanistic understanding has fostered exploration of therapeutic interventions—ranging from immune modulation to pro-angiogenic and anabolic agents—to rejuvenate healing in elderly patients.

Research from Nature Portfolio

Seminal work using heterochronic parabiosis has revealed that exposure of aged rodents to youthful circulation restores fracture repair. Young haematopoietic cells engrafted into older hosts reverse age-related deficits in osteoblastic differentiation and callus formation. Central to this rejuvenation is temporal modulation of β-catenin signalling during the early repair phase: attenuating excessive β-catenin activation in aged fractures enhances osteogenesis and accelerates biomechanical recovery. These findings underscore a systemic component to skeletal ageing and identify β-catenin as a tractable target for improving bone regeneration in elderly individuals.

Fracture Healing Mechanisms in Aging Models publication trend

The graph below shows the total number of articles in fracture healing mechanisms in aging models across all publications each year (not limited to Nature Index journals).

Technical terms

Callus: Temporary, fibrous and cartilaginous tissue that bridges a bone fracture and is gradually replaced by mineralised bone.

Endochondral ossification: Process in which cartilage is formed and then replaced by bone during the reparative phase of fracture healing.

Angiogenesis: Formation of new blood vessels from pre-existing vasculature, crucial for delivering cells and nutrients to the healing site.

Macrophage: Innate immune cell that orchestrates inflammation, debris clearance and release of cytokines guiding repair.

Osteoclast: Multinucleated cell responsible for bone resorption during the remodelling phase.

Heterochronic parabiosis: Experimental joining of the circulatory systems of young and old animals to study systemic factors in ageing.

TREM2: Triggering receptor expressed on myeloid cells 2, a surface receptor on macrophages involved in regulation of inflammation and tissue repair.

β-Catenin signalling: Wnt-dependent pathway that regulates osteoblast differentiation and bone formation.

Interleukin-22 (IL-22): Cytokine produced by immune cells that can modulate inflammation and influence tissue regeneration.

References

1. Age‐related changes to macrophage subpopulations and TREM2 dysregulation characterize attenuated fracture healing in old mice. Aging Cell (2024).
2. Cilostazol Stimulates Angiogenesis and Accelerates Fracture Healing in Aged Male and Female Mice by Increasing the Expression of PI3K and RUNX2. International Journal of Molecular Sciences (2024).
3. Exposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin. Nature Communications (2015).
4. Local immune cell contributions to fracture healing in aged individuals – A novel role for interleukin 22. Experimental & Molecular Medicine (2022).