The peripheral immune system plays a critical role in aging and in the response to
brain injury. Emerging data suggest inflammatory responses are exacerbated in older animals following
ischemic stroke; however, our understanding of these age-related changes is poor. In this work, we demonstrate marked differences in the composition of circulating and infiltrating leukocytes recruited to the ischemic brain of old male mice after
stroke compared to young male mice. Blood neutrophilia and neutrophil invasion into the brain were increased in aged animals. Relative to infiltrating monocyte populations, brain-invading neutrophils had reduced phagocytic potential, and produced higher levels of
reactive oxygen species and extracellular matrix-degrading
enzymes (i.e., MMP-9), which were further exacerbated with age. Hemorrhagic transformation was more pronounced in aged versus young mice relative to
infarct size. High numbers of
myeloperoxidase-positive neutrophils were found in postmortem human brain samples of old (> 71 years)
acute ischemic stroke subjects compared to non-ischemic controls. Many of these neutrophils were found in the brain parenchyma. A large proportion of these neutrophils expressed MMP-9 and positively correlated with
hemorrhage and
hyperemia. MMP-9 expression and hemorrhagic transformation after
stroke increased with age. These changes in the myeloid response to
stroke with age led us to hypothesize that the bone marrow response to
stroke is altered with age, which could be important for the development of effective
therapies targeting the immune response. We generated heterochronic bone marrow chimeras as a tool to determine the contribution of peripheral immune senescence to age- and
stroke-induced
inflammation. Old hosts that received young bone marrow (i.e., Young → Old) had attenuation of age-related reductions in bFGF and
VEGF and showed improved locomotor activity and gait dynamics compared to isochronic (Old → Old) controls. Microglia in young heterochronic mice (Old → Young) developed a senescent-like phenotype. After
stroke, aged animals reconstituted with young marrow had reduced behavioral deficits compared to isochronic controls, and had significantly fewer brain-infiltrating neutrophils. Increased rates of hemorrhagic transformation were seen in young mice reconstituted with aged bone marrow. This work suggests that age alters the immunological response to
stroke, and that this can be reversed by manipulation of the peripheral immune cells in the bone marrow.