Age-dependent differences in microglial responses to systemic inflammation are evident as early as middle age

Abstract

Whereas age increases microglial inflammatory activities and impairs their ability to effectively regulate their immune response, it is unclear at what age these exaggerated responses begin. We tested the hypotheses that augmented microglial responses to inflammatory challenge are present as early as middle age and that repeated stimulation of primed microglia in vivo would reveal microglial senescence. Microglial gene expression was investigated in a mouse model of repeated systemic inflammation induced by intraperitoneal injection of bacterial lipopolysaccharide (LPS). Following LPS, microglia from middle-aged mice (9-10 mo) displayed larger increases in Tnfα, Il-6, and Il-1β gene expression compared with young adults (2 mo). Similar results were observed in the spleens of middle-aged mice, indicating that exaggeration of both central and peripheral immune responses are already evident at early middle age. Interestingly, despite greater proinflammatory responses to the first LPS challenge in the aged mice, there were no age-dependent differences in either microglia or spleen following a subsequent LPS dose, suggesting that animals at this age retain the ability to effectively control their immune response following repeated challenge. The exacerbated microglial immune response to systemic inflammation at early middle age suggests that the CNS may be vulnerable to age-dependent alterations earlier than previously appreciated.

Sex differences in the peripheral and central immune responses following lipopolysaccharide treatment in pubertal and adult CD‐1 mice

“…Furthermore, senescent mice have been shown to be the most sensitive to LPS lethality and produce significantly elevated plasma TNFα and nitric oxide levels in comparison to young and mature mice (Chorinchath et al, 1996). Similarly, middle‐aged mice display exaggerated peripheral and central immune responses for TNFα, IL‐6, and IL‐1β production in their microglia and spleens compared to young adults following LPS treatment (Nikodemova et al, 2016).…”

Biosystems Study of the Molecular Networks Underlying Hippocampal Aging Progression and Anti-aging Treatment in Mice

“…The most common theories for aging include telomere attrition, endocrine disorders, and oxidative stress ( Patel et al, 2015 ). It has been suggested that low-grade inflammation, which is characterized by increased levels of inflammatory cytokines in response to environmental signals, contributes to aging processes ( Nikodemova et al, 2016 ). The chronic inflammation eventually initiates immune-senescence in both the immune and central nervous system, resulting in the functional decline of the immune system with age ( Regulski, 2017 ).…”

Neuroprotection in Perimenopausal Women

“…activation M1 (classical) to M2 (alternative) type [68] or it is a maladaptive microglia activation [69], or a shift from neuroprotection to neurotoxicity, underlining chronic neuroinflammation and parainflammation, which is different in women and men [70,71]. The shift is connected to proinflammatory cytokines and oxidative-nitrosative stress, which plus elevated levels of complement pathway components and other immune factors plays a key pathophysiological role in promoting cognitive dysfunction by enhancing endothelin, Amyloid-β deposition, cerebral amyloid angiopathy, aberrant synapse elimination in the hippocampus [72], and blood-brain barrier disruption.…”