American Society for Peripheral Nerve
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Age-related Changes in Nerve Regeneration After Peripheral Nerve Injury in Murine Models. A Systematic Review.
Karla Cristina Maita, MD1; Francisco R. Avila, MD1; Ricardo A. Torres-Guzman, MD1; John P. Garcia, MD1; Abdullah Sami Eldaly, MD2; Olivia Ho, MD2; Forte Antonio, MD3
1Mayo Clinic, Jacksonville, FL; 2Mayo Clinic in Florida, Jacksonville, FL; 3Mayo Clinic Florida, Jacksonville, FL

Introduction: The influence of aging on regenerative tissue processes has been well established. After a peripheral nerve injury, Schwann cells are responsible for regenerating the peripheral nervous system. In addition to the cellular chemotaxis that promotes an ideal microenvironment for nerve healing. With age, Schwann cell (SC) functions decline, and a cellular imbalance decreases the regenerative ability of the peripheral nervous system. However, the specific molecular mechanisms involved in this decreased cellular performance have not been well understood. This systematic review aims to evaluate the influence of age on peripheral nerve regeneration and the underlying molecular mechanism.
Methods: Four databases were systematically queried following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in July 2022. Studies evaluating the underlying mechanisms implied in nerve regeneration after a sciatic nerve injury in elderly murine models were included. In vitro experimental studies were excluded.
Results: After the removal of duplication, 110 studies were identified. Eleven articles fulfilled our inclusion and exclusion criteria. Eight studies were performed in mice and 3 using rats’ models. A reduction in gene expression of SOX10, VEFG, S100, and NGF in the proximal stump of the damaged nerve in the elderly group was observed. Furthermore, a decrease in the expression of myelin protein and axonal transport of cytoskeletal proteins leads to poor myelin production in the aged group. Additionally, hypomyelinated nerve fibers were seen in the aged group related to a downregulation of Neuregulin-1 levels. Furthermore, failure in the activation and proliferation of SC due to a reduction in the expression and phosphorylation of the c-Jun gene caused delayed regeneration in the elderly model. Finally, a lack of balance between pro-and anti-inflammatory cytokines was higher in the aged group compared to the young group, affecting the macrophage’s clearance capacity and subsequent suppression of the SC function and axonal regeneration. Thus, the peripheral nerve regeneration in the young group was considerably higher than in the aged group in all the studies.
Conclusion: Age-related changes in Schwann cells performance decrease the regenerative capacity of the peripheral nervous system in murine models. The chronic inflammatory stage, impaired macrophage function, and the inefficient SC dedifferentiation in aged animals lead to a decline in the regenerative response of the peripheral nervous system in case of an injury.


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