In this open access commentary, the authors discuss efforts to uncover the mechanisms by which microglia in the aging brain are primed to undertake inflammatory responses, more so than those in the young brain. This may be due in part towards increased numbers of senescent microglia, secreting pro-inflammatory signals. This tendency towards an exaggerated response to potential threats causes harm to neural and cognitive function. The age-related dysfunction of microglia is thought to be an important contributing factor to the progression of neurodegeneration in later life, particular given the growing evidence for chronic inflammation in the brain to be involved in the development of neurodegenerative conditions.
The inflammatory response that occurs systemically and in the brain is exacerbated as a result of aging. The underlying inflammation, which is actually heightened with age, is believed to be a precursor to neurodegenerative diseases like Alzheimer's disease. Moreover, in diseases in which inflammation plays a critical role, the aging population seems to be more vulnerable.
Previous research has shown that systemic infection can affect the central nervous system (CNS); studies have shown evidence of cognitive decline following systemic inflammation. Cognitive decline seems to occur more frequently in the aged population after infection, likely due to the microglial priming that occurs with age. Primed microglia have a heightened pro-inflammatory gene profile and a decrease in neuroprotective factors, which causes an exaggerated response to stimuli. Based on this evidence, it was hypothesized that systemic infection would produce a greater pro-inflammatory response in the brain of aged mice, and that this heightened response occurs because aged mice are lacking in the expression of microglial-specific anti-inflammatory genes.
In a mouse model of systemic infection, researchers observed an increase in microglial cell count and a more pro-inflammatory environment in middle-aged infected mice. This study is consistent with previous evidence showing that inflammaging, or age-related inflammation, is naturally heightened in the nervous system. Moreover, the authors disproved their hypothesis that anti-inflammatory microglia-specific genes are responsible for the elevated inflammatory response in aged brains since the expression of anti-inflammatory mediators was elevated in middle-aged brains following infection. Thus, the cause for the increase in pro-inflammatory genes remains to be elucidated.