Recent evidence indicates aging sensitizes microglial cells to signals from the peripheral immune system, resulting in an exaggerated neuroinflammatory response and behavioral pathology during peripheral infection.5,8,11
Thus, to promote healthy aging and facilitate recovery after peripheral infection, it is vital that new strategies be envisioned to mitigate the dysregulated communication between the immune system and brain in elderly subjects. Therefore, the goal of the present study was to determine if consuming a diet supplemented with the polyphenol resveratrol afforded aged mice protection from the excessive production of IL-1β in the brain and severe behavioral and cognitive deficits that occur during infection. The significant results showed that dietary supplementation of resveratrol inhibited the production of IL-1β in the periphery and brain as well as the deficits in spatial working memory when LPS was administered to aged mice to mimic a peripheral infection. Resveratrol was further shown to inhibit IL-1β production by LPS-stimulated microglia in vitro
. Thus, the present findings in aged mice suggest dietary resveratrol can constrain the central response to signals from the peripheral immune system and promote recovery after peripheral infection.
Markers of inflammation have been reported to increase in both the peripheral blood39,40
with advancing age. In the periphery, this is due in part to the increased capacity of mononuclear cells in elderly subjects to produce proinflammatory cytokines.42
This is also the case in the brain as microglia, which are derived from mononuclear myeloid progenitors, from aged mice produced higher levels of proinflammatory cytokines both in the absence and presence of immune stimuli.41,43
Peripheral injection of LPS has been found to cause an exaggerated inflammatory cytokine response in the aged brain.5,8
Moreover, anorexia, depression-like behavior, and deficits in hippocampal-dependent learning and memory are more evident in old mice than in young adults after peripheral LPS administration.5,8,44
Importantly, this was confirmed in the present study, because aged mice compared to young adults had: (1) higher circulating levels of IL-1β in the absence and presence of LPS stimulation; (2) higher levels of IL-1β mRNA in the hippocampus in the absence and presence of LPS stimulation; (3) LPS-induced sickness behavior of a greater magnitude and duration; and (4) LPS-induced deficits in spatial working memory. Thus, the model appeared to be optimal for assessing the ability of resveratrol to mitigate the interaction between the peripheral immune system and brain in aged subjects.
In this study we adopted a pragmatic approach by delivering resveratrol as a dietary supplement. Similar to other polyphenols, the oral bioavailability of resveratrol is low due to rapid excretion and extensive metabolism into various glucuronide and sulfate conjugates.45,46
Nonetheless, moderate consumption of red wine, where resveratrol is highly concentrated, is associated with reduced risk of cardiovascular disease and cancer.47,48
Moreover, several reports have confirmed orally administered resveratrol to be absorbed and cross the blood–brain barrier and incorporate into the brain.49–52
The antiinflammatory effects of resveratrol in aged mice could be linked to its ability to inhibit factors involved in gene transcription such as mitogen-activated protein kinase (MAPK), AP-1, and NF-κB.25
Resveratrol affects NF-κB by inhibiting Iκ-B kinase, thereby preventing translocation of NF-κB into the nucleus.25,53
How this occurs is not clear; however, it may be that resveratrol activates SIRT1, an enzyme of the sirtuin class of nicotinamide adenine dinucleotide (NAD)+
-dependent histone deacetylases, which deacetylates NF-κB, thereby inactivating the transcription factor.54,55
Recently, Adler et al.56
demonstrated that inhibition of NF-κB signaling in old mice reverted the tissue characteristics and global gene expression to those of young mice. This kind of “rejuvenation” suggests that the continuous activation of NF-κB signaling could promote the aging process. Several studies have indicated that SIRT1 is a potent inhibitor of NF-κB transcription.32,54
The signaling link between SIRT1 and NF-κB is especially interesting with respect to aging because according to a number of studies SIRT1 acts to extend lifespan by inhibiting NF-κB signaling, and this is sufficient to reverse gene expression changes associated with age in mice.54,56,57
It is important to note that resveratrol did not inhibit the effects of LPS in young adults. This is important because immunological and behavioral responses to infection are intended to help the host contend against infective agents. However, in LPS-treated old mice, resveratrol reduced IL-1β in the periphery and brain and improved locomotor behavior and hippocampal-dependent spatial working memory. Accordingly, resveratrol may prove to be neuroprotective against age-related neuroinflammation by downregulating NF-κB signaling and restoring the response to LPS to that of their younger cohorts.
Regardless of the mechanism, the current findings suggest that dietary supplementation with resveratrol may play an important role in reversing the deleterious effects of infection on behavior and cognition in elderly subjects. These findings may also support the role of natural compounds as a possible preventative and/or complementary therapy for several neurodegenerative diseases caused by neuroinflammation.