Fig. 1

The differences in the acute inflammatory phase after fracture between the young and aging state. a After a bone fracture, the acute inflammatory phase is initiated, resulting in the formation of a hematoma at the fracture site and the infiltration of mobilized polymorphonuclear neutrophils (PMNs) to clear dead cells and debris. PMNs secrete pro-inflammatory chemokines, which attract macrophages, stem cells, and other progenitor cells to the site of injury to facilitate repair. Macrophages (M0) can be activated into two major subtypes: pro-inflammatory M1 and anti-inflammatory M2 macrophages. Initially, macrophages exhibit an M1 phenotype, but as the healing process progresses, they polarize toward an M2 phenotype. This shift is associated with a decrease in pro-inflammatory cytokines and an increase in anti-inflammatory cytokines. As the levels of anti-inflammatory cytokines rise, mesenchymal stem cells (MSCs) differentiate into osteoblasts, promoting new bone formation, while osteoclasts break down the damaged bone tissue. This coordinated process allows for the remodeling of the bone, ultimately leading to the restoration of bone structure and function. b Aging is associated with a persistent, low-grade, subclinical systemic inflammatory state, as evidenced by elevated circulating pro-inflammatory cytokines at baseline. The persistence of high expression of inflammatory cytokines prolongs the inflammation phase. Aged macrophages show increased sensitivity and responsiveness to inflammatory signals, increased susceptibility to oxidative stress, and lower proliferation. The persistent chronic inflammation that results from the failure to repolarize macrophages from the M1 to M2 phenotype leads to increased osteoclast activation and decreased osteoblast formation, resulting in increased bone resorption and decreased bone formation during healing. In aging, the decreased number and proliferative capacity of MSCs further contribute to impaired bone healing. Aged MSCs are more likely to become senescent and have lower osteogenic potential. Thus, the interplay between macrophages, osteoclasts, and MSCs is altered with aging, leading to impaired bone healing