Impaired regeneration in aged nerves: Clearing out the old to make way for the new.

Although many observational studies have shown that peripheral nerve regeneration is impaired with aging, underlying cellular and molecular mechanisms have remained obscure until recently. A series of recent genetic, live imaging and heterochronic parabiosis experiments are providing new insights into the underlying mechanisms of reduced regenerative capacity with aging. These studies show that Schwann cells pose a primary impediment to axon regeneration in older animals as they fail to support regenerating axons, while the contribution from macrophages remains an unresolved issue. Neurons do not appear to have an intrinsic defect of axonal elongation with aging but are impaired when they encounter an inhibitory environment, suggesting that therapeutic approaches to improve intrinsic neuronal regeneration capacity across inhibitory environments, as it is being done in central nervous system regeneration, can improve peripheral nerve regeneration as well. As in many aspects of neuroscience therapeutics development, a combinatorial approach may yield the best outcomes for nerve regeneration in aged individuals.