Michael Ngan

Background: The average age of a traumatic spinal cord injury (SCI) has increased from 29 to 43 years old from the 1970s to 2015.¹ Unfortunately, this increase in age at time of injury is associated with decreased potential for recovery post injury.³ Moreover, the mortality rate one year after an SCI in those under 65 years old is 2-3% and increases to 25-39% in those over 65 years old.¹ As the average age of those experiencing SCI continues to increase, it is imperative that we understand the effects of aging on the pathophysiology of SCI. The immune response may be a critical area of divergence across age groups that could influence recovery outcomes. Age-dependent pathways that have been identified for wound healing involve monocyte-derived macrophages and microglia.⁵ In addition, the ability to regulate reactive oxygen species in an older age group would result in increased tissue damage.⁶

Objective(s): In this literature review, we explored how the roles of macrophages and microglia altered due to aging.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2025 using the following keywords: “spinal cord injury”, “aging”

Results: Studies used single cell RNA sequencing of approximately 77,000 CD45+ cells to show the immune cell population response to an SCI.⁵ Microglial subtypes identified included homeostatic, proliferating, inflammatory A, and inflammatory B microglia. While the number of monocyte derived macrophages increased in both young and older mice three days post-SCI,⁵ SCI increased homeostatic and inflammatory microglia A in younger mice while inflammatory microglia B were increased in older mice.⁷ The Ki67 proliferating microglia were also more present in the young mice three days post injury,⁵ and afterwards the proportion of activated microglia in young mice decreased.⁵ Older mice had an increased proportion of recruiting and inflammatory macrophages.⁵ The total number, free glutathione, and reduced glutathione levels were also reduced in the older mice, which decreasing their ability to respond to the increase in oxidative stress after injury.⁶ Based on these data, studies have tested the therapeutic potential of apocynin, which is a NADPH oxidase inhibitor, in older mice.⁸ Treatment with apocynin increased locomotor recovery, decreased lesion volume, and reduced ROS production in 14 month old mice after SCI.⁸ Monocyte derived macrophages also decreased in the older mice with apocynin.⁸ There was no apocynin effect on P2Y12 homeostatic microglia.⁸

Conclusion: There is a significant change in the inflammatory response to SCI with aging.^5,7 Homeostatic microglia appear to be more prevalent in young mice given SCI while activated microglia are prevalent in older mice. These age-dependent inflammatory responses affect recovery of function after SCI, and should inform the therapeutic approach .^5,7 The positive effects of apocynin therapy on recovery in aged but not young mice with SCI underscores the importance of age as a modifying variable. Indeed, decreased spinal glutathione levels were only seen in older mice. Therapies targeting reactive oxygen species and oxidative stress in the spinal cord⁶ may selectively benefit the older population. In sum, targeting the immune response is a promising strategy for improving recovery after SCI, but age must be considered in developing the therapeutic approach.

Works Cited:

1. Gaudet AD, Fonken LK, Ayala MT, Maier SF, Watkins LR. Aging and miR-155 in mice influence survival and neuropathic pain after spinal cord injury. Brain Behav Immun. 2021;97:365-370. doi:10.1016/j.bbi.2021.07.003
2. Lei Z, Ritzel RM, Li Y, Li H, Faden AI, Wu J. Old age alters inflammation and autophagy signaling in the brain, leading to exacerbated neurological outcomes after spinal cord injury in male mice. Brain Behav Immun. 2024;120:439-451. doi:10.1016/j.bbi.2024.06.023
3. Kirshblum S, Snider B, Eren F, Guest J. Characterizing Natural Recovery after Traumatic Spinal Cord Injury. J Neurotrauma. 2021;38(9):1267-1284. doi:10.1089/neu.2020.7473
4. Anjum A, Yazid MD, Fauzi Daud M, et al. Spinal Cord Injury: Pathophysiology, Multimolecular Interactions, and Underlying Recovery Mechanisms. Int J Mol Sci. 2020;21(20):7533. Published 2020 Oct 13. doi:10.3390/ijms21207533
5. Salvador AFM, Dykstra T, Rustenhoven J, et al. Age-dependent immune and lymphatic responses after spinal cord injury. Neuron. 2023;111(14):2155-2169.e9. doi:10.1016/j.neuron.2023.04.011
6. Stewart AN, Glaser EP, Mott CA, et al. Advanced Age and Neurotrauma Diminish Glutathione and Impair Antioxidant Defense after Spinal Cord Injury. J Neurotrauma. 2022;39(15-16):1075-1089. doi:10.1089/neu.2022.0010
7. Shao L, Chang Y, Liu J, et al. scRNA-Seq reveals age-dependent microglial evolution as a determinant of immune response following spinal cord injury. Brain Res Bull. 2024;219:111116. doi:10.1016/j.brainresbull.2024.111116
8. Zhang B, Bailey WM, McVicar AL, Stewart AN, Veldhorst AK, Gensel JC. Reducing age-dependent monocyte-derived macrophage activation contributes to the therapeutic efficacy of NADPH oxidase inhibition in spinal cord injury. Brain Behav Immun. 2019;76:139-150. doi:10.1016/j.bbi.2018.11.013