The age factor in axonal repair after spinal cord injury: A focus on neuron-intrinsic mechanisms

doi:10.1016/j.neulet.2016.11.003

Neuroscience Letters

Volume 652, 23 June 2017, Pages 41-49

https://doi.org/10.1016/j.neulet.2016.11.003 Get rights and content

Abstract

Age is an important consideration for recovery and repair after spinal cord injury. Spinal cord injury is increasingly affecting the middle-aged and aging populations. Despite rapid progress in research to promote axonal regeneration and repair, our understanding of how age can modulate this repair is rather limited. In this review, we discuss the literature supporting the notion of an age-dependent decline in axonal growth after central nervous system (CNS) injury. While both neuron-intrinsic and extrinsic factors are involved in the control of axon growth after injury, here we focus on possible intrinsic mechanisms for this age-dependent decline.

Introduction

Age is an important factor for spinal cord injury (SCI) and repair. SCI is increasingly inflicted in the middle aged and aging populations [21], [90]. The average age of incidence for SCI 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), partly due to an increasingly active older population. In a census study initiated by the Christopher and Dana Reeve Foundation, the average age of people in the United States who reported being paralyzed due to a SCI is now at ∼48, with the peak age group of 40–49 followed closely by the 50–59 age group (Fig. 1). Together, the 40 and above age groups represent about 75% of all people with a paralyzing SCI. Thus, whereas SCI used to preferentially affect young individuals, today this condition most widely impacts older individuals and especially the middle-aged group. These changing demographics call for a critical need to better understand how age and aging impact recovery and repair after SCI.

The field of SCI has certainly recognized the importance of age in both the basic and clinical arenas [24], [30], [38], [39], [40], [101]. However, our understanding of how age and aging impact repair and recovery after SCI is still rather limited. In particular, despite the critical importance of axon regeneration in central nervous system (CNS) repair and the rapid progress in understanding its molecular regulation [6], [9], [11], [61], [64], [73], [74], [80], [84], [89], [91], [93], a major gap exists in our knowledge of how age impacts CNS axon regeneration. This is in large part due to the fact that CNS axons even in young adult mammals have a very limited natural ability to regenerate after injury. Meanwhile, most of the studies in the field use young animals as the model system, corresponding at best to teenagers/young adults in humans. It is understandable that studying how aging impacts spinal cord repair can be intimidating: it is extremely time and resource consuming, and experimental manipulations may be less likely to have a detectable effect relative to experiments performed in young animals.

As this dichotomy in age between human spinal cord injury populations and experimental animal models will inevitably impede translational efforts for restorative therapies, it is of special importance to better understand the impact age has on spinal cord repair. A parallel can be drawn in the field of stroke research, where age has been recognized as an important variable in translating basic research findings into clinical practice [31]. In this review, we will discuss the evidence for an age-dependent decline in axon growth after CNS injury. Although both neuron-intrinsic and -extrinsic factors are likely to play significant roles in this age-dependent decline, here we focus on potential neuron-intrinsic mechanisms as the first step to start a discourse on this important topic.

Section snippets

Age-dependent decline in axon growth after injury in diverse systems

In model organisms, axon regeneration has been reported to decline with age. In aging zebrafish, axon regeneration occurs at a reduced speed with an increased latency, both of which were tentatively attributed to factors intrinsic to the neurons [37]. Similarly, in C. elegans, efficiency of axon regeneration declines with age, and intra-neuronal mechanisms seem to be at play [13]. An important question in the relationship between aging and axon regeneration is whether molecular pathways

Candidate neuron-intrinsic signaling pathways in the age-dependent decline

As discussed above, PTEN deletion has recently been used to create an enhanced axonal growth state in order to demonstrate an age-dependent decline in CNS regeneration after SCI [34]. This reduced regeneration in older mice may be due to a slower speed of regeneration or a prolonged latency between axonal injury and regeneration [25], although this remains to be firmly established. Regardless, regeneration is diminished in older mice with PTEN deletion. While changes in neuron-extrinsic factors

Other neuron-intrinsic considerations

In addition to the specific neuron-intrinsic molecular species and pathways listed above, other neuron-intrinsic properties may influence axon regeneration specifically in aging adults (Fig. 3).

Conclusion

It is well accepted in several model organisms and the mammalian PNS that age negatively impacts axon regeneration after injury. This observation has now been extended to the mammalian CNS. Our knowledge of the age-dependent decline in axon regeneration in the context of spinal cord injury is rather limited, although testable hypotheses exist. As the average age of incidence of SCI and the average age of people living with a paralyzing SCI are increasing, there is a strong need to better

Acknowledgments

This work was supported by grants from NIH/NINDS (R01NS054734, R01NS093055), Craig H. Neilsen Foundation (190181 and 384971) and Wings for Life Foundation (WFL-US-014/13). J.M.M. is supported by the UCSD Neuroplasticity of Aging Training Program (T32AG000216).

References (112)

P. Arlotta et al.
Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo
Neuron
(2005)
M. Bains et al.
Antioxidant therapies in traumatic brain and spinal cord injury
Biochim. Biophys. Acta
(2012)
R.S. Balaban et al.
Mitochondria, oxidants, and aging
Cell
(2005)
S. Belin et al.
Injury-induced decline of intrinsic regenerative ability revealed by quantitative proteomics
Neuron
(2015)
F. Bradke et al.
Editorial overview: development and regeneration: nervous system development and regeneration
Curr. Opin. Neurobiol.
(2014)
A.B. Byrne et al.
Insulin/IGF1 signaling inhibits age-dependent axon regeneration
Neuron
(2014)
A.D. Cash et al.
Microtubule reduction in Alzheimer’s disease and aging is independent of tau filament formation
Am. J. Pathol.
(2003)
C.C. Chen et al.
FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor
Dev. Cell
(2010)
C. De-Fraja et al.
STAT signalling in the mature and aging brain
Int. J. Dev. Neurosci.: Off. J. Int.Soc. Dev. Neurosci.
(2000)
M.J. DeVivo et al.
Trends in new injuries, prevalent cases, and aging with spinal cord injury
Arch. Phys. Med. Rehabil.
(2011)

I. Gavazzi et al.

Axonal regeneration from transplanted sympathetic ganglia is not impaired by age

Exp. Neurol.

(1993)

T. Genovese et al.

Increased oxidative-related mechanisms in the spinal cord injury in old rats

Neurosci. Lett.

(2006)

C.G. Geoffroy et al.

Evidence for an age-dependent decline in axon regeneration in the adult mammalian central nervous system

Cell Rep.

(2016)

S.L. Groah et al.

Sinal cord injury medicine. 5. Preserving wellness and independence of the aging patient with spinal cord injury: a primary care approach for the rehabilitation medicine specialist

Arch. Phys. Med. Rehabil.

(2002)

Y.S. Gwak et al.

Locomotor recovery and mechanical hyperalgesia following spinal cord injury depend on age at time of injury in rat

Neurosci. Lett.

(2004)

N. Hay

Interplay between FOXO, TOR, and Akt

Biochim. Biophys. Acta

(2011)

E.R. Hollis et al.

IGF-I gene delivery promotes corticospinal neuronal survival but not regeneration after adult CNS injury

Exp. Neurol.

(2009)

Y.W. Hu et al.

MicroRNA-210 promotes sensory axon regeneration of adult mice in vivo and in vitro

Neurosci. Lett.

(2016)

A. Jaerve et al.

Differential effect of aging on axon sprouting and regenerative growth in spinal cord injury

Exp. Neurol.

(2011)

M. Kawabuchi et al.

Age affects reciprocal cellular interactions in neuromuscular synapses following peripheral nerve injury

Ageing Res. Rev.

(2011)

T.B. Le et al.

Effects of pathway and neuronal aging on the specificity of motor axon regeneration

Exp. Neurol.

(2001)

Y. Lu et al.

Signaling regulations of neuronal regenerative ability

Curr. Opin. Neurobiol.

(2014)

X. Luo et al.

Enhanced transcriptional activity and mitochondrial localization of STAT3 Co-induce axon regrowth in the adult central nervous system

Cell Rep.

(2016)

K. Maiese et al.

The Wnt signaling pathway: aging gracefully as a protectionist?

Pharmacol. Ther.

(2008)

I.G. McQuarrie et al.

Retardation in the slow axonal transport of cytoskeletal elements during maturation and aging

Neurobiol. Aging

(1989)

S. Milde et al.

Axonal transport declines with age in two distinct phases separated by a period of relative stability

Neurobiol. Aging

(2015)

H. Nawabi et al.

Doublecortin-like kinases promote neuronal survival and induce growth cone reformation via distinct mechanisms

Neuron

(2015)

H.M. Oh et al.

STAT3 protein interacts with class O forkhead transcription factors in the cytoplasm and regulates nuclear/cytoplasmic localization of FoxO1 and FoxO3a proteins in CD4(+) T cells

J. Biol. Chem.

(2012)

M.W. Painter et al.

Diminished Schwann cell repair responses underlie age-associated impaired axonal regeneration

Neuron

(2014)

K. Patel et al.

MicroRNA let-7 downregulates STAT3 phosphorylation in pancreatic cancer cells by increasing SOCS3 expression

Cancer Lett.

(2014)

B.A. Payne et al.

Mitochondrial dysfunction in aging: much progress but many unresolved questions

Biochim. Biophys. Acta

(2015)

A. Pestronk et al.

Effects of aging on nerve sprouting and regeneration

Exp. Neurol.

(1980)

M.M. Siegenthaler et al.

Myelin pathogenesis and functional deficits following SCI are age-associated

Exp. Neurol.

(2008)

P.D. Smith et al.

SOCS3 deletion promotes optic nerve regeneration in vivo

Neuron

(2009)

E. Verdu et al.

The effect of aging on efferent nerve fibers regeneration in mice

Brain Res.

(1995)

M.R. Andrews et al.

Axonal localization of integrins in the CNS is neuronal type and age dependent

eNeuro

(2016)

F.M. Bareyre et al.

In vivo imaging reveals a phase-specific role of STAT3 during central and peripheral nervous system axon regeneration

Proc. Natl. Acad. Sci. U. S. A.

(2011)

I. Bentov et al.

Insulin-like growth factor-i regulates Kruppel-like factor-6 gene expression in a p53-dependent manner

Endocrinology

(2008)

O.G. Bhalala et al.

microRNA-21 regulates astrocytic response following spinal cord injury

J. Neurosci.: Off. J. Soc. Neurosci.

(2012)

M.G. Blackmore et al.

Kruppel-like Factor 7 engineered for transcriptional activation promotes axon regeneration in the adult corticospinal tract

Proc. Natl. Acad. Sci. U. S. A.

(2012)

A.S. Brack et al.

Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis

Science

(2007)

A. Bratic et al.

The role of mitochondria in aging

J. Clin. Invest.

(2013)

A. Caricasole et al.

Induction of Dickkopf-1 a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer’s brain

J. Neurosci.: Off. J. Soc. Neurosci.

(2004)

A.C. Carrano et al.

A Kruppel-like factor downstream of the E3 ligase WWP-1 mediates dietary-restriction-induced longevity in Caenorhabditis elegans

Nat. Commun.

(2014)

T. Chiba et al.

Amyloid-beta causes memory impairment by disturbing the JAK2/STAT3 axis in hippocampal neurons

Mol. Psychiatry

(2009)

F. Deak et al.

Aging, synaptic dysfunction, and insulin-like growth factor (IGF)-1

J. Gerontol. Series A Biol. Sci. Med. Sci.

(2012)

S. Di Giovanni et al.

The tumor suppressor protein p53 is required for neurite outgrowth and axon regeneration

EMBO J.

(2006)

S. Di Giovanni et al.

p53-Dependent pathways in neurite outgrowth and axonal regeneration

Cell Tissue Res.

(2012)

J.D. Dolbow et al.

The effects of aging and electrical stimulation exercise on bone after spinal cord injury

Aging Dis.

(2013)

K. Du et al.

Pten deletion promotes regrowth of corticospinal tract axons 1 year after spinal cord injury

J. Neurosci.: Off. J. Soc. Neurosci.

(2015)

Cited by (34)

Minimally invasive corneal neurotization for neurotrophic keratopathy: The potential effect of age, denervation chronicity and lesion location
2023, American Journal of Ophthalmology Case Reports
Neurotrophic keratopathy (NK) is an uncommon but challenging clinical condition characterized by altered corneal nerves and sensation leading to corneal damage. Corneal neurotization, a surgical technique that aims to “re-innervate” the cornea, has gained increasing popularity in view of the potential to permanently improve or even restore the normal corneal sensation. In this study, we aimed to report the outcomes of two cases of NK that underwent indirect minimally invasive corneal neurotization (MICN) with a sural nerve autograft, and to provide plausible explanations for the observed clinical outcomes.
This was an interventional case series of two patients who underwent MICN for severe unilateral NK. The MICN technique was adapted from the technique originally described by Elbaz et al., in 2014. Clinical severity of NK was graded according to Mackie's grading system. Corneal sensation was measured using the Cochet-Bonnet esthesiometer (0–60mm) and corneal nerves were examined using in vivo confocal microscopy (IVCM) with Heidelberg HRT3 Rostock Corneal Module. Patient 1 was a 70-year-old man with a right grade III NK following trigeminal nerve decompression for trigeminal neuralgia. Patient 2 was a 62-year-old man with a left grade II NK following a left-sided acoustic neuroma resection. The denervation time was 23 years for both patients. Following the MICN surgery, none of the patients achieved sustained improvement in the corneal sensation (though patient 1 achieved a transient improvement in central corneal sensation to 20mm at 4 months' postoperative before returning to 0mm at 6 months' postoperative). IVCM did not reveal any changes in the corneal nerve density and morphology post-MICN.
Based on our observations and the literature, we postulate that long denervation time, proximal injury to the trigeminal nerve and older patient age may serve as poor prognostic factors for MICN. As CN is being increasingly adopted in clinical practice for treating NK, understanding of these potential factors will facilitate better risk-benefit stratification and patient counselling. Future larger studies are required to elucidate these findings.
Targeting PTEN but not SOCS3 resists an age-dependent decline in promoting axon sprouting
2022, iScience
Citation Excerpt :
At a superficial level, our current study appears to support that hypothesis because, unlike regenerating axons, sprouting axons do not need to navigate through or around a hostile injury terrain. However, the current data indicate that neuron-intrinsic factors are also at play (Geoffroy et al., 2017), since different signaling pathways (i.e., PTEN/mTOR vs. SOCS3/STAT3) are differentially affected by age in regulating sprouting. In addition to resisting an age-dependent decline in enhancing CST sprouting when initiated pre-injury, PTEN deletion also does so when applied 6 weeks after injury as a model of delayed molecular intervention.
Axonal repair is critical for functional recovery after injury of the CNS. We previously reported that neuronal PTEN deletion exhibits an age-dependent decline in promoting axon regeneration from the corticospinal tract (CST). How sprouting of uninjured axons, a naturally occurring form of axonal repair, is impacted by age is unknown. We assessed CST sprouting after unilateral pyramidotomy in PTEN and/or SOCS3-deleted mice at different ages. While PTEN deletion enhances sprouting independently of age, SOCS3 deletion loses its sprouting-promoting effect with age. The synergistic effect of PTEN/SOCS3 co-deletion on CST sprouting is rapidly lost with increased age. Overall, promoting sprouting appears more robust across age than regeneration, yet distinct molecular pathways are differentially impacted by age. Importantly, six-week delayed PTEN deletion promotes CST sprouting across age groups, supporting a clinically relevant time frame for this neural repair strategy independently of age.
The use of viral vectors to promote repair after spinal cord injury
2022, Experimental Neurology
Citation Excerpt :
Although the extrinsic environment plays a major role in the diminished ability for axon growth, intrinsic factors are also involved. It is known that intrinsic factors play a role in the difference between the robust regenerative capabilities of the mammalian peripheral nervous system (PNS) and the CNS (Geoffroy et al., 2017). Pathways that promote axon growth during development are downregulated with age, leading to impaired regenerative capabilities for the mature CNS.
Spinal cord injury (SCI) is a devastating event that can permanently disrupt multiple modalities. Unfortunately, the combination of the inhibitory environment at a central nervous system (CNS) injury site and the diminished intrinsic capacity of adult axons for growth results in the failure for robust axonal regeneration, limiting the ability for repair. Delivering genetic material that can either positively or negatively modulate gene expression has the potential to counter the obstacles that hinder axon growth within the spinal cord after injury. A popular gene therapy method is to deliver the genetic material using viral vectors. There are considerations when deciding on a viral vector approach for a particular application, including the type of vector, as well as serotypes, and promoters. In this review, we will discuss some of the aspects to consider when utilizing a viral vector approach to as a therapy for SCI. Additionally, we will discuss some recent applications of gene therapy to target extrinsic and/or intrinsic barriers to promote axon regeneration after SCI in preclinical models. While still in early stages, this approach has potential to treat those living with SCI.
Particular precautions and the role of intraoperative neuromonitoring in cervical cord injury in elder recreational cyclist: A case report
2022, International Journal of Surgery Case Reports
Citation Excerpt :
However, the clinical improvement had not improved as fast as the signals. It is postulated that the aging process may have a negative impact on axonal repair after spinal cord injury [15]. Unfortunately, during this time gap before the regeneration process can be expected, bradycardia as the most common cardiac arrhythmia following CCI complicates the post-operative period in this patient.
The trend in cycling nowadays affects all age groups. However, special precautions must be considered in the elderly group. Minor trauma to the cervical region can cause severe neurological deterioration, leading to fatality because of the pre-existing degenerative process.
We present a case of a 61-year-old male recreational cyclist with acute onset of tetraplegia following a minor fall. The radiological result revealed a long-standing degenerative process. Unfortunately, the patient deceased due to the sequelae of the paralysis and cardiac event despite our prompt surgical decompression and the improvement shown on intraoperative neuromonitoring.
The degenerative process can aggravate cervical cord injury even in its mildest form of injury. In this study, immediate improvement was detected by the intraoperative neuromonitoring (IONM) - although the clinical improvement had not improved yet as the general condition is poor.
The elder cycling population is increasing. Safety measures and injury avoidance are advisable along with expert consultation before the exercise. In a pre-existing degenerative condition of the cervical, a special precaution is also needed during the exercise. If the surgery has been indicated, the use of intraoperative neuromonitoring is found to be useful to guide the decompression and potentially beneficial as a predictive value for the clinal outcome.
Designing neuroreparative strategies using aged regenerating animal models
2020, Ageing Research Reviews
Citation Excerpt :
Age-related changes in the regulation of intrinsic components involved in axonal growth are suggested to play a role, including the phosphate and tensin homologue (PTEN)/mechanistic target of rapamycin (mTOR), Wnt/related to receptor tyrosine kinase (Ryk), insulin/insulin-like growth factor (IGF) and suppressor of cytokine signaling 3 (SOCS3)/signal transducer and activator of transcription 3 (STAT3) signaling pathways, the Krüppel-like factors, p53 and miRNAs. Moreover, alterations in neuronal viscosity and axonal transport may contribute to this age-associated decline in CNS regeneration as increased axonal stiffness and a decline in axonal transport have been described to occur in the aged peripheral nervous system (PNS) (Geoffroy et al., 2017; Lamoureux et al., 2010; Milde et al., 2015). In a rare case, Jaerve and colleagues demonstrated that when spinal axons are induced to regenerate by an anti-scarring treatment, axonal sprouting, but not axonal regrowth into the lesion area, is significantly reduced in aged rats after spinal cord insult.
In our ever-aging world population, the risk of age-related neuropathies has been increasing, representing both a social and economic burden to society. Since the ability to regenerate in the adult mammalian central nervous system is very limited, brain trauma and neurodegeneration are often permanent. As a consequence, novel scientific challenges have emerged and many research efforts currently focus on triggering repair in the damaged or diseased brain. Nevertheless, stimulating neuroregeneration remains ambitious. Even though important discoveries have been made over the past decades, they did not translate into a therapy yet. Actually, this is not surprising; while these disorders mainly manifest in aged individuals, most of the research is being performed in young animal models. Aging of neurons and their environment, however, greatly affects the central nervous system and its capacity to repair. This review provides a detailed overview of the impact of aging on central nervous system functioning and regeneration potential, both in non-regenerating and spontaneously regenerating animal models. Additionally, we highlight the need for aging animal models with regenerative capacities in the search for neuroreparative strategies.
Knockdown PEG10 deteriorates H<inf>2</inf>O<inf>2</inf>-injury of PC-12 cells by targeting miR-34a-5p/TLX
2020, Molecular Immunology
Spinal cord injury (SCI) is a neurological disease with high incidence and disability. In this paper, we made a foundational study in long non-coding RNA paternally expressed gene 10 (lncRNA PEG10) at PC-12 cells.
We used CCK8, flow cytometry, migration and invasion assay to detect changes at the cellular level. PEG10, microRNA-34a-5p (miR-34a-5p) and TLX transfected by transfection assay and amplified by real-time quantitative PCR (qRT-PCR). TLX expression and proteins about apoptosis and pathways were investigated by Western blot. Additionally, the relationship between PEG10 and miR-34a-5p, miR-34a-5p and TLX were examined through luciferase assay.
H₂O₂-injury model was established. Knockdown PEG10 deteriorated H₂O₂-injury. miR-34a-5p was confirmed as a target of PEG10 and miR-34a-5p inhibitor remitted PEG10-induced H₂O₂-injury. Moreover, TLX was confirmed as a target miR-34a-5p and TLX remitted H₂O₂-injury. At last, TLX worked in H₂O₂-injury via Smad and Wnt/β-catenin pathways.
Knockdown PEG10 remitted H₂O₂-injury of PC-12 cells by targeting miR-34a-5p/TLX, and the behavior may be involved in Smad and Wnt/β-catenin pathways.

View all citing articles on Scopus

View full text

Review articleThe age factor in axonal repair after spinal cord injury: A focus on neuron-intrinsic mechanisms

Abstract

Introduction

Section snippets

Age-dependent decline in axon growth after injury in diverse systems

Candidate neuron-intrinsic signaling pathways in the age-dependent decline

Other neuron-intrinsic considerations

Conclusion

Acknowledgments

Neuron

Biochim. Biophys. Acta

Cell

Neuron

Curr. Opin. Neurobiol.

Neuron

Am. J. Pathol.

Dev. Cell

Int. J. Dev. Neurosci.: Off. J. Int.Soc. Dev. Neurosci.

Arch. Phys. Med. Rehabil.

Exp. Neurol.

Neurosci. Lett.

Cell Rep.

Arch. Phys. Med. Rehabil.

Neurosci. Lett.

Biochim. Biophys. Acta

Exp. Neurol.

Neurosci. Lett.

Exp. Neurol.

Ageing Res. Rev.

Exp. Neurol.

Curr. Opin. Neurobiol.

Cell Rep.

Pharmacol. Ther.

Neurobiol. Aging

Neurobiol. Aging

Neuron

J. Biol. Chem.

Neuron

Cancer Lett.

Biochim. Biophys. Acta

Exp. Neurol.

Exp. Neurol.

Neuron

Brain Res.

Axonal localization of integrins in the CNS is neuronal type and age dependent

eNeuro

In vivo imaging reveals a phase-specific role of STAT3 during central and peripheral nervous system axon regeneration

Proc. Natl. Acad. Sci. U. S. A.

Insulin-like growth factor-i regulates Kruppel-like factor-6 gene expression in a p53-dependent manner

Endocrinology

microRNA-21 regulates astrocytic response following spinal cord injury

J. Neurosci.: Off. J. Soc. Neurosci.

Kruppel-like Factor 7 engineered for transcriptional activation promotes axon regeneration in the adult corticospinal tract

Proc. Natl. Acad. Sci. U. S. A.

Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis

Science

The role of mitochondria in aging

J. Clin. Invest.

Induction of Dickkopf-1 a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer’s brain

J. Neurosci.: Off. J. Soc. Neurosci.

A Kruppel-like factor downstream of the E3 ligase WWP-1 mediates dietary-restriction-induced longevity in Caenorhabditis elegans

Nat. Commun.

Amyloid-beta causes memory impairment by disturbing the JAK2/STAT3 axis in hippocampal neurons

Mol. Psychiatry

Aging, synaptic dysfunction, and insulin-like growth factor (IGF)-1

J. Gerontol. Series A Biol. Sci. Med. Sci.

The tumor suppressor protein p53 is required for neurite outgrowth and axon regeneration

EMBO J.

p53-Dependent pathways in neurite outgrowth and axonal regeneration

Cell Tissue Res.

The effects of aging and electrical stimulation exercise on bone after spinal cord injury

Aging Dis.

Pten deletion promotes regrowth of corticospinal tract axons 1 year after spinal cord injury

J. Neurosci.: Off. J. Soc. Neurosci.

Review article
The age factor in axonal repair after spinal cord injury: A focus on neuron-intrinsic mechanisms