Citation

Ritzel RM, Doran SJ, Glaser EP, Meadows VE, Faden AI, Stoica BA, Loane DJ. Neurobiol. Aging 2019; 77: 194-206.

Affiliation

Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: dloane@som.umaryland.edu.

Copyright

(Copyright © 2019, Elsevier Publishing)

DOI

10.1016/j.neurobiolaging.2019.02.010

PMID

30904769

Abstract

After traumatic brain injury (TBI), individuals aged over 65 years show increased mortality and worse functional outcomes compared with younger persons. As neuroinflammation is a key pathobiological mechanism of secondary injury after TBI, we examined how aging affects post-traumatic microglial responses and functional outcomes. Young (3-month-old) and aged (18-month-old) male C57Bl/6 mice were subjected to moderate-level controlled cortical impact or sham surgery, and neurological function was evaluated. At 72 hours after injury, brain, blood, and spleen leukocyte counts were assessed ex vivo using flow cytometry. Aged mice demonstrated more severe deficits in forelimb grip strength, balance and motor coordination, spontaneous locomotor activity, and anxiety-like behavior. These animals also exhibited more robust microglial proliferation and significantly higher numbers of brain-infiltrating leukocytes. Microglia in aged mice showed impairments in phagocytic activity and higher production of interleukin-1β (IL-1β). Infiltrating myeloid cells in aged TBI mice also had deficits in phagocytosis but showed diminished proinflammatory cytokine production and greater reactive oxygen species production. Expression of several senescence markers (Bcl-2, p16^ink4a, p21^cip1a, lipofuscin, and H2AX [pS139]) was increased with age and/or TBI in both microglia and injured cortex. Although there was no difference in the number of circulating blood neutrophils as a function of age, young mice exhibited more pronounced TBI-induced splenomegaly and splenic myeloid cell expansion. Thus, worse post-traumatic behavioral outcomes in aged animals are associated with exaggerated microglial responses, increased leukocyte invasion, and upregulation of senescence markers.

Copyright © 2019 Elsevier Inc. All rights reserved.

Language: en

Keywords

Aging; Behavior; Microglia; Neuroinflammation; Traumatic brain injury