Spinal cord injury is increasingly inflicted in older populations. The average age of incidence for spinal cord injury has risen substantially in recent years, from ∼29 in the 1970s to ∼42 since 2010 in the United States (National Spinal Cord Injury Statistical Center) due to an increasingly active older population. This changing demographic calls for a critical need to better understand how aging impacts recovery and repair after spinal cord injury.
Despite the central importance of axon regeneration in spinal cord repair, how aging impacts CNS axon regeneration is not well understood, largely because CNS axons, even in young adult mammals, naturally have a very limited ability to regenerate after injury. The recent discovery of neuron-intrinsic factors whose manipulation reproducibly promotes axon regeneration in the CNS has made it possible to address this question.
To assess the impact of increased age on CNS axon regeneration, researchers asked whether genetic Pten deletion, a molecular manipulation that promotes significant CNS axon regeneration in young adult mammals, remains effective in older animals (up to 12–18 months old). PTEN is a negative regulator of the mTOR (mammalian target of rapamycin) signaling pathway. Neuronal mTOR activity undergoes development-dependent decline and is further downregulated after axonal injury in the adult CNS. Genetic Pten deletion in young animals prevents axotomy-induced reduction of mTOR activity and promotes the regeneration of both retinal ganglion and corticospinal tract (CST) axons after CNS injury.
Researchers examined the effect of age on axon regeneration in the mammalian CNS using both the CST and the rubrospinal tract (RST) as the model systems. The data indicate that aging may dissociate neuron-intrinsic growth state and axon regeneration in Pten-deleted mice, neuronal properties previously considered inseparable.
Specifically, while Pten deletion in middle-aged to aging mice continues to promote a neuron-intrinsic growth state as assessed by mTOR activity, neuronal soma size, and axonal growth proximal to a spinal cord injury, it loses effectiveness in promoting axon regeneration distal to the injury as compared with young mice accompanied by increased expression of astroglial and inflammatory markers at the injury site.
These results reveal an age-dependent decline in CNS axon regeneration and implicate changes in neuron-extrinsic influences in this age-dependent decline.
http://www.cell.com/cell-reports/abstract/S2211-1247(16)30284-4
Evidence for an Age-Dependent Decline in Axon Regeneration in the Adult Mammalian CNS
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