| In the peripheral nervous system (PNS), aging is associated with a number of disorders, including a decline in regenerative capacity after injury. Although this decline has been observed in both rodents and humans for decades, the cellular and molecular underpinnings of this defect have remained elusive. As such, the goal of this thesis was to elucidate, at least in part, how aging impinges on axonal regeneration.;In this work, we demonstrate a progressive, age-dependent slowing in the recovery of sensory and motor function following peripheral nerve injury. A systematic investigation of the possible causes follows, focusing on the potential roles of neuronal intrinsic growth, immune cell function, and Schwann cell responses. Unexpectedly, an array of in vitro, in vivo and in silico experiments provide no evidence that neuronal intrinsic growth is altered with aging. In addition, exposure of youthful circulating factors to aged mice fails to rescue the age-associated phenotype, implying that macrophage-intrinsic defects are unlikely to be involved. In contrast to these results, functional recovery in aged animals can be fully rejuvenated by transplantation of young nerve grafts. Likewise, aged nerve grafts transplanted into young hosts results in diminished axonal regeneration. Microarray profiling of young and aged sciatic nerves reveals a highly perturbed transcriptional landscape, with the regulation of genes associated with the function of Schwann cells being particularly aberrant. These alterations are mirrored functionally, as aged Schwann cells fail to efficiently de-differentiate and engulf myelin. Finally, it is also noted that the protein expression of a key regulator of Schwann cell injury responses, c-Jun, is altered in aging nerves. Taken together, this thesis work shows that extrinsic factors are sufficient to rejuvenate age-associated decline in nerve regeneration, and suggest Schwann cells as key effectors of the aging PNS. |
