Chronic inflammation is thought to be one of the major roads by which a few forms of low-level molecular damage, the root causes of aging, give rise to a much broader and more varied range of cell and tissue dysfunctions. Short-term inflammation is a necessary part of both regeneration and the protective activities of the immune system, and is vital to health. Long-term chronic inflammation that arises as a maladaptive reaction to the damage of aging is a different story, however. It changes the behavior of cells for the worse, disrupting regenerative processes, damaging organs, and accelerating the development and progression of age-related disease.
Inflammation is particularly well studied in the context of neurodegeneration, the gradual failure of the brain and the mind that it hosts. The central nervous system, brain included, is segregated from the rest of the body by the blood-brain barrier, and, accordingly, the immune system of the brain is somewhat different to that of the rest of the body. Cells that carry out the usual functions expected of the immune system, including mounting a defense against pathogens and clearing up debris, also participate in neural activity, such as by assisting in creation and maintenance of synaptic connections. Thus chronic inflammation in the brain can have worse and more complex detrimental effects than is the case in other organs.
The open access paper noted here is an example of continued efforts to understand the exact signals and causes that underlie the well established relationship between chronic inflammation in aging and the progression of neurodegenerative conditions. Inflammation arises as the result of signals passed between cells, most of which are at least cataloged at this time, even if a complete picture of this highly dynamic web of signaling is still under construction. Which of these signals are important, and is cognitive decline a function of the presence of these signals regardless of age, or are older individuals more negatively affected by a given level of inflammatory signaling, indicating that other mechanisms of deterioration are at work?
Mounting evidence associates cognitive impairment with systemic immune activation. For example, elevated serum levels of pro-inflammatory cytokines, including interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α) and C-reactive protein (CRP), lead to impairments in overall cognition as well as impairments in specific functions, such as reduced processing speed, executive function, and memory. These associations between systemic inflammation and cognitive impairment have been found in young, middle-aged, and older adults. Furthermore, within older adults, this inflammation-cognition link has also been documented. However, to our knowledge, previous studies have not directly examined the mediatory role of systemic inflammation on cognitive aging.
Systemic inflammation leads to elevated circulating pro-inflammatory cytokines, including IL-6, TNF-α, and CRP, which can interact with the central nervous system through three three pathways that, when stimulated peripherally, will activate microglia and astrocytes in the brain to produce pro-inflammatory cytokines, propagating the signal into the neural environment. This leads to comparable inflammation levels in the brain and the periphery. Elevated neuroinflammation can result in structural and functional impairment in the brain, such as hippocampal atrophy and increased substantia nigra activity, both of which have been associated with cognitive deficits.
Going beyond previous work, the present study took a novel methodological approach by examining the mediation of systemic inflammation (i.e., serum levels of IL-6, TNF-α and CRP) on age-related cognitive impairments (i.e., deficits in processing speed and short-term memory). We found that systemic inflammation partially explained differences in cognitive performance associated with increased age. In particular, IL-6 levels accounted for the age-group difference in processing speed. Further, IL-6 levels accounted for the age-related differences in processing speed within the older but not the young age group. Neither of the remaining two examined inflammatory biomarkers (i.e., TNF-α, CRP) nor short-term memory yielded any significant effects.
Two possible mechanisms may underlie the observed moderated mediation. First, age may increase the impact of systemic inflammation on cognition. However, in the present study we did not find a significant age-moderation of the effect of IL-6 levels on processing speed. That is, the association between IL-6 levels and processing speed was comparable between young and older adults. Similarly, a previous study showed that an experimentally-induced elevation in inflammatory cytokine response consistently hindered reaction times among young participants. This suggests that systemic inflammation produces similar impairments regardless of individual age.
Second, systemic inflammation levels increase with age, possibly because older adults face more immune challenges and become increasingly likely to display mild chronic inflammation. With chronic conditions, primed microglia can yield deleterious effects on their local neuro-environment, eliciting even greater inflammation, which may further prime microglia. This, in combination with continued accumulation of immune challenges, implies that inflammation levels, and their subsequent influence on cognition, may accelerate with time. Previous longitudinal studies, however, found no associations between systemic inflammation levels and the rate of cognitive decline. Importantly, these earlier studies focused on cohorts of older adults only. Further, while participants were tracked for about 10 year periods, this time span may have been too short to capture causal effects. Following from this argument, findings from the present study, which investigated a wider age range, showed that IL-6 levels partially accounted for the variance in processing speed between young and older adults.