Aging is a complex process, which was once considered inevitable and irreversible. However, studies in mice, using heterochronic parabiosis, argue that some effects of aging may, in fact, be reversible. In this model the vascular system of a young mouse is connected to the vascular system of an aged mouse. These studies have been particularly informative about the role that aging has in the response to injury. In 2005 Conboy et al. (1) found that delays in the regenerative potential of muscle stem (satellite) cells and liver hepatocytes in aged mice could be reversed when these animals were parabiosed with young mice. These studies established that some effects of aging on progenitor and mature cells are reversible. They also demonstrated that the factors that produced these effects were transferrable through the circulation. Using lineage tracing it was shown that the tissue regeneration phenotype of aged tissue after heterochronic parabiosis was due to the responses of resident cells and not to the responses of cells that transferred into the aged mice from the younger animal.
In subsequent work some researchers identified growth differentiation factor 11 (GDF11), a member of the BMP/TGFβ superfamily, as a protein in serum that restored the young features of cardiac (2) and skeletal muscle (3) in aged animals. However, others have disputed these results (4). Hence, the role of GDF11 in the response of aged cells to heterochronic parabiosis is controversial.
Now Baht et al. (5) has used heterochronic parabiosis to examine whether the differences in the repair response to fracture between young and old mice are reversible. They were interested in this question because the rate of fracture repair in old mice is significantly slower than in young mice. These authors found that heterochronic parabiosis reversed the fracture repair phenotype of aged mice and enhanced their osteoblastic differentiation capacity.
Furthermore, they demonstrated that the capacity to revert the fracture repair process and the osteogenic potential of aged animals to that of young mice occurred when bone marrow cells from young animals were adoptively transferred into old mice. Hence, bone marrow cells appear to produce factors that reverse the aging response during fracture repair and enhance the rate that bone is formed. It did not appear that aged mice produce factors that diminish the fracture repair process to any great degree since transfer of older bone marrow cells into young mice had only a small inhibitory effect on the fracture repair process.
Using a targeted osteoblast ablation strategy, the authors found that destruction of osteoblasts in the host prevented the repair process, while ablation of osteoblasts in the graft had little effect on the rate of fracture repair. This experiment demonstrated that the interaction of young bone marrow with aged mesenchymal cells is critical for the reversion of the fracture response from that seen in aged mice to that seen in young animals.
Exactly what the factor or factors are that young animals produce to enhance the fracture repair process remains unknown. However, the fact that these experiments demonstrate their existence provides hope that they will eventually be identified. It is therefore possible to envision a future in which diseases of aging such as fracture nonunion or the poor osseous integration of orthopaedic or dental implants into bone may be treated with agents that mimic the effects of youthful serum on the fracture repair process.
Farmington, CT, USA
We Are as Young as Our Serum
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