Aging is often accompanied by cognitive decline, memory impairment and an increased susceptibility to neurodegenerative disorders. Most of these age-related alterations have been associated with deleterious processes such as changes in cytokine expression.

Cytokines are cell-signaling proteins secreted to mediate the response of the body's defense system to injury, and to regulate diverse inflammatory processes. These cell-signaling proteins include pro-inflammatory cytokines, such as TNFα, IL1β and IL6, and anti-inflammatory cytokines, such as IL10. Short-term inflammatory reactions in response to injuries are adaptive and essential for survival, but chronic inflammation can be harmful.

In the aging brain, pro-inflammatory cytokines have been found to be chronically increased. Higher IL6 levels were observed in the cortex, hippocampal formation and cerebellum of aged mice when compared to juvenile and adult mice. Additionally, reduced IL10 levels have been detected in the aged brain. Evidence indicates that age-related decline in IL10 levels may contribute to the increased expression of brain IL6 in aged mice.

This perturbation in pro- and anti-inflammatory balance may represent one of the mechanisms that contribute to age-related neuronal dysfunction and the brain's vulnerability to diseases. Indeed, increased levels of pro-inflammatory cytokines are reported in neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and other chronic conditions. Consequently, pharmacological and non-pharmacological interventions targeting the cytokines and their signaling pathways have been suggested for therapeutic purposes.

There is a great deal of evidence showing the capacity of physical exercise to reduce (or ameliorate) the risk of common age-associated disorders. Exercise may be a potential intervention to improve the cognitive performance of the elderly, and to reduce the onset or progression of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. These beneficial effects of exercise during aging should be related to changes in cytokine brain expression.

Recent investigation showed that exercise can shift the inflammatory response in the brain of Tg2576 Alzheimer mice. In view of these observations, scientists conducted a study to investigate the levels of TNFα, IL1β, IL6 and IL10 in the hippocampal formation - a highly plastic region of the brain that is linked to cognitive and emotional processes - of senescent rats submitted to an aerobic exercise program. In this study they have investigated the hippocampal levels of TNFα, IL1β, IL6 and IL10 in senescent rats submitted to an aerobic exercise program of 10 days on a treadmill.

Quantitative immunoassay analyses showed that physical exercise increased the IL10 levels in the hippocampal formation of aged rats when compared to control rats. The hippocampal levels of pro-inflammatory cytokines IL1β, IL6 and TNFα were not statistically different between studied groups.

Studies using young rodents have shown that exercise can alter brain expression of pro-inflammatory cytokines. It was reported that progressive exercise training led to reductions in IL1β concentrations in the hippocampus and IL6 concentrations in the cerebellum. On the other hand, other studies have not found significant differences in IL1β, IL6 and TNFα expression in the young brain of sedentary and trained rodents.

The latter results accord with the found data and with previous findings in non-transgenic aged mice with free access to running wheels for 3 weeks. However, it is important to point out that a significant reduction in the hippocampal IL1β/IL10, IL6/IL10 and TNFα/IL10 ratio was detected in aged animals from the exercise group as compared with the control group.

Taken together, these findings indicate a favorable effect of physical exercise on the hippocampal pro- and anti-inflammatory balance of aged rats.

Inflammatory cytokines can exert negative or positive effects on brain functions. These effects are dependent on numerous factors, including the type of cytokine produced, the functional state and type of stimulated cells, and the concentration and duration of exposure to the cytokines. In particular, the aged brain has been characterized by increased levels of pro-inflammatory cytokines. The upregulation of pro-inflammatory cytokines may contribute to unsuccessful maintenance of neuronal communication and to cell death by modulating the NMDA and AMPA receptors. The over activation of these glutamate receptors can induce neurodegenerative processes and amplify neuronal vulnerability through increased intracellular calcium concentration, strongly deregulated in aging. Furthermore, it has been described that pro-inflammatory cytokines impair the aged brain's ability to maintain hippocampal long-term potentiation (LTP), a critical physiological process involved in memory consolidation.

The inflammation-induced LTP impairment is accompanied by enhanced activity of stress-activated protein kinases and reactive oxygen species. Interestingly, promising data have shown that inflammation-linked LTP impairment can be reversed by intracerebroventricular infusion of the anti-inflammatory cytokine IL10. As mentioned before, anti-inflammatory cytokines are significantly reduced in the aged brain. This anti-inflammatory downregulation has been related to increased expression of pro-inflammatory cytokines and neuronal injury. Indeed, IL10 knockout mice are more sensitive to neuronal damage and behavioral deficits.

These findings suggest that IL10 reduction in the aged brain might result in neuronal dysfunction and vulnerability. Thus, interventions to increase IL10 levels could have great therapeutic value.

In the present study, scientists observed that an aerobic exercise program of 10 days enhanced IL10 levels and reduced the pro-/anti-inflammatory cytokine ratio in the hippocampal formation of aged rats. The importance of anti-inflammatory response induced by exercise indicates its potential therapeutic action for age-related brain inflammatory imbalance as well as to reduce the risk of neuroinflammation-linked disorders. Some factors could contribute to this anti-inflammatory effect of exercise in the aging brain. These factors may include a large number of cell-signaling proteins induced by exercise, which are known to be associated with neuronal survival and proliferation, and synaptic plasticity. Among them, growth-related proteins such as neurotrophins have been considered the most likely candidates in mediating the effects of exercise on brain functions.

Neurotrophins are a heterogeneous group of endogenous proteins secreted to regulate cellular processes of proliferation, development and differentiation. These proteins are synthesized by both neurons and glial cells and allow neurons to receive adequate nutrition to grow, develop or regenerate themselves. Previous data in young rats show that a few days of exercise result in a significant upregulation of neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF).

Considering recent findings showing that stimulation of dendritic cells with NGF and BDNF induces IL10 release, it is possible that this experimental data could also be correlated to the increase of NGF and BDNF levels in the hippocampal formation of aged rats submitted to physical exercise. In support of this idea, it has been observed that short bouts of exercise may increase the hippocampal levels of the BDNF gene and protein in aged rats.

Keywords: exercise, treadmill, brain, aging, plasticity, cytokine, inflammation.