Aging exacerbates neutrophil pathogenicity in ischemic stroke

Abstract

Ischemic stroke is major cause of disability and mortality worldwide, and aging is strong risk factor for poor post-stroke outcome. Neutrophils traffic rapidly to the brain following ischemic stroke, and recent evidence has suggested that aging may alter neutrophil function after tissue injury. In this study, we hypothesize that aging enhances the pro-inflammatory function of neutrophils, directly contributing to the poorer outcomes seen in aging patients. We utilized demographic data and biological specimens from ischemic stroke patients and an experimental mouse model to determine the correlation between age, neutrophil function and stroke outcomes. In ischemic stroke patients, age was associated with increased mortality and morbidity and higher levels of neutrophil-activating cytokines. In mice, aged animals had higher stroke mortality and morbidity, higher levels of neutrophil-activating cytokines and enhanced generation of neutrophil reactive oxygen species compared to young mice. Finally, depletion of neutrophils via a specific monoclonal antibody after ischemic stroke led to long-term benefits in functional outcome in aged male and female animals, with no benefit observed in young. These results demonstrate that aging is associated with augmented neutrophil pathogenicity in ischemic stroke, and that neutrophil-targeted therapies may confer greater benefit in aged subjects.

Role of Neutrophils on the Ocular Surface

“…Neutrophil extracellular traps remove the old vessels to promote remodeling [ 111 ]. However, aging drives neutrophils to be pathogenic, contributing to vascular diseases [ 112 , 113 ]. The intestinal microtome regulates neutrophil aging by enhancing C-X-C motif chemokine receptor 4 and reducing L-selectin [ 114 ].…”

Integrated Multi-Omics for Novel Aging Biomarkers and Antiaging Targets

“…MiR-19a-3p has been recommended as a biomarker for ischemic stroke, and the gene pathways targeted by miRNAs related to inflammation, coagulation, and platelet activation have been identified [ 116 ]. Considering the association between stroke and age and that the elderly population has a higher risk of stroke, the identification of miRNAs can be used for various age-related diseases to subsequently discover biomarkers for disease treatment and prevention [ 117 ]. Similarly, human hearing loss is related to the expression of miR-34a and miR-21, which may be potential biomarkers of inflammation [ 118 , 119 ].…”

Potential of Mesenchymal Stem Cells in the Rejuvenation of the Aging Immune System

“…The neutrophils also have significantly elevated activation of TLR and NOD-like receptor (NLR), and NF-kB signaling pathways and express higher levels of TLR4 surface antigen [ 84 ]. Next, Roy-O’Reilly et al stated that aging augments the ROS production in circulating neutrophils and suppresses the neutrophil clearance mechanism which results in an overabundance of circulating neutrophils [ 94 ]. Under normal conditions, the circulating neutrophils will be cleared in the bone marrow, liver, and spleen.…”