Macrophages of the innate immune system, cells derived from monocytes, are involved in many processes in tissue beyond merely hunting down invading pathogens. They are also important to the processes of tissue maintenance regeneration following injury. Like all aspects of the immune system, macrophage behavior becomes dysregulated with age, a consequence of changes in the signaling environment that result from the accumulation of molecular damage that causes aging. Here, researchers demonstrate that this aging of the immune system degrades the ability of the peripheral nervous system to regenerate, and that exposing macrophages to a more youthful tissue environment reverses some of this lost regenerative capacity. Further, they identify a little of the regulatory biochemistry involved in this aspect of degenerative aging.

The regenerative capacity of injured peripheral nerves is diminished with aging. To identify factors that contribute to this impairment, we compared the immune cell response in young versus aged animals following nerve injury. First, we confirmed that macrophage accumulation is delayed in aged injured nerves which is due to defects in monocyte migration as a result of defects in site-specific recruitment signals in the aged nerve. Interestingly, impairment in both macrophage accumulation and functional recovery could be overcome by transplanting bone marrow from aged animals into young mice. That is, upon exposure to a youthful environment, monocytes/macrophages originating from the aged bone marrow behaved similarly to young cells.

Transcriptional profiling of aged macrophages following nerve injury revealed that both pro- and anti-inflammatory genes were largely downregulated in aged compared to young macrophages. One ligand of particular interest was macrophage-associated secreted protein (MCP1), which exhibited a potent role in regulating aged axonal regrowth in vitro. Given that macrophage-derived MCP1 is significantly diminished in the aged injured nerve, our data suggest that age-associated defects in MCP1 signaling could contribute to the regenerative deficits that occur in the aged nervous system.