Abstract
BackgroundMultiple studies have shown that plasma levels of the pro-inflammatory cytokine interleukin-6 (IL-6) are elevated in patients with important and prevalent adverse health conditions, including atherosclerosis, diabetes, obesity, obstructive sleep apnea, hypertension, and frailty. Higher plasma levels of IL-6, in turn, increase the risk of many conditions associated with aging including age-related cognitive decline. However, the mechanisms underlying this association between IL-6 and cognitive vulnerability remain unclear.Methods and FindingsWe investigated the role of IL-6 in brain aging in young (4 mo) and aged (24 mo) wild-type C57BL6 and genetically-matched IL-6−/− mice, and determined that IL-6 was necessary and sufficient for increased neuronal expression of the superoxide-producing immune enzyme, NADPH-oxidase, and this was mediated by non-canonical NFκB signaling. Furthermore, superoxide production by NADPH-oxidase was directly responsible for age-related loss of parvalbumin (PV)-expressing GABAergic interneurons, neurons essential for normal information processing, encoding, and retrieval in hippocampus and cortex. Targeted deletion of IL-6 or elimination of superoxide by chronic treatment with a superoxide-dismutase mimetic prevented age-related loss of PV-interneurons and reversed age-related cognitive deficits on three standard tests of spatial learning and recall.ConclusionsPresent results indicate that IL-6 mediates age-related loss of critical PV-expressing GABAergic interneurons through increased neuronal NADPH-oxidase-derived superoxide production, and that rescue of these interneurons preserves cognitive performance in aging mice, suggesting that elevated peripheral IL-6 levels may be directly and mechanistically linked to long-lasting cognitive deficits in even normal older individuals. Further, because PV-interneurons are also selectively affected by commonly used anesthetic agents and drugs, our findings imply that IL-6 levels may predict adverse CNS effects in older patients exposed to these compounds through specific derangements in inhibitory interneurons, and that therapies directed at lowering IL-6 may have cognitive benefits clinically.
Highlights
Multiple studies have found that circulating markers of inflammation, including interleukin-6 (IL-6), are increased in older individuals[1,2,3] and are strongly associated with enhanced risk of disease and disability[3]
Present results indicate that IL-6 mediates age-related loss of critical PV-expressing GABAergic interneurons through increased neuronal NADPH-oxidase-derived superoxide production, and that rescue of these interneurons preserves cognitive performance in aging mice, suggesting that elevated peripheral IL-6 levels may be directly and mechanistically linked to long-lasting cognitive deficits in even normal older individuals
Because PV-interneurons are selectively affected by commonly used anesthetic agents and drugs, our findings imply that IL-6 levels may predict adverse CNS effects in older patients exposed to these compounds through specific derangements in inhibitory interneurons, and that therapies directed at lowering IL-6 may have cognitive benefits clinically
Summary
Multiple studies have found that circulating markers of inflammation, including interleukin-6 (IL-6), are increased in older individuals[1,2,3] and are strongly associated with enhanced risk of disease and disability[3]. Longitudinal studies on centenarians and long-lived human populations indicate that longevity is inversely correlated with plasma levels of IL-6[2,4], and that higher plasma levels of this interleukin increase the risk of many conditions associated with aging[5], including age-related cognitive decline[3,6,7,8]. Elevated circulating IL-6 enhances risk of stroke and dementia in older individuals[9] and has been shown to predict future cognitive decline[6]. Despite this body of literature, the specific mechanisms which link peripheral IL-6 and central nervous system impairment are still largely unknown. The mechanisms underlying this association between IL-6 and cognitive vulnerability remain unclear
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