nutrients, microglia aging, and brain aging

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  • Review ArticleNutrients, Microglia Aging, and Brain Aging

    Zhou Wu,1 Janchun Yu,2 Aiqin Zhu,3 and Hiroshi Nakanishi1

    1Department of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan2Department of General Surgery, Peking UnionMedical College Hospital, Chinese Academy ofMedical Sciences, Beijing 100730, China3Institution of Geriatric Qinghai Provincial Hospital, Xining 810007, China

    Correspondence should be addressed to Zhou Wu; and Janchun Yu;

    Received 25 September 2015; Revised 21 December 2015; Accepted 31 December 2015

    Academic Editor: Trevor A. Mori

    Copyright 2016 Zhou Wu et al.This is an open access article distributed under theCreative CommonsAttribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

    As the life expectancy continues to increase, the cognitive decline associated with Alzheimers disease (AD) becomes a big majorissue in the world. After cellular activation upon systemic inflammation, microglia, the resident immune cells in the brain, start torelease proinflammatory mediators to trigger neuroinflammation. We have found that chronic systemic inflammatory challengesinduce differential age-dependent microglial responses, which are in line with the impairment of learning and memory, even inmiddle-aged animals. We thus raise the concept of microglia aging. This concept is based on the fact that microglia are thekey contributor to the acceleration of cognitive decline, which is the major sign of brain aging. On the other hand, inflammationinduces oxidative stress and DNA damage, which leads to the overproduction of reactive oxygen species by the numerous types ofcells, including macrophages and microglia. Oxidative stress-damaged cells successively produce larger amounts of inflammatorymediators to promote microglia aging. Nutrients are necessary for maintaining general health, including the health of brain. Theintake of antioxidant nutrients reduces both systemic inflammation and neuroinflammation and thus reduces cognitive declineduring aging. We herein review our microglia aging concept and discuss systemic inflammation and microglia aging. We proposethat a nutritional approach to controlling microglia aging will open a new window for healthy brain aging.

    1. Introduction

    The cognitive decline associated with aging and Alzheimersdisease (AD) will be a major issue in aging societies aroundthe world as the life expectancy continues to increase.A better understanding of the factors that accelerate thiscognitive decline will help in the development of strategiesfor preventing or delaying this cognitive decline. Microglia,the resident mononuclear phagocytes in the brain, are chron-ically or pathologically activated to influence the neuronalenvironment. There is increasing evidence that activatedmicroglia produce excessive reactive oxygen species (ROS)during aging [1] and hypoxia [26], resulting in the nuclearfactor-B- (NF-B-) dependent excessive production ofproinflammatory mediators, including interleukin-1 (IL-1), tumor necrosis factor- (TNF-), and interleukin-6 (IL-6) [711]. Furthermore, activated microglia-mediated neu-roinflammation is closely associated with the pathogenesisof AD pathogenesis [12], because activated microglia trigger

    neuroinflammation to promote neuronal damage and thedeposition of amyloid (A) [13, 14]. Moreover, anti-inflammatory agents improve the cognitive functions of ADpatients [15, 16].

    It is well accepted that chronic systemic inflammation canalter the neuroinflammation in the brain [17, 18]. In additionto being associated with systemic diseases such as atheroscle-rosis and diabetes, rheumatoid arthritis (RA), periodontitis,and inflammatory bowel disease (IBD) also directly initiateor hasten the progression of AD [19]. A clinical study hasdemonstrated the impact of RA and periodontitis on AD[20], and recent experimental studies have clarified the routesof inflammatory signal transduction from chronic systemicinflammation to the brain [17, 18, 20].

    We have recently found that natural products, such aspropolis, inhibit the hypoxia-induced production of proin-flammatory mediators by microglia through the inhibitionofmitochondria-derived ROS generation and the subsequentactivation of the NF-B signaling pathway. Furthermore, we

    Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2016, Article ID 7498528, 9 pages

  • 2 Oxidative Medicine and Cellular Longevity

    have found that RNSP, a traditional Tibetan medicine whichis composed of 70 herbal components, improves the cognitivefunction in middle-to-moderate AD patients living at highaltitude by reducing the levels of proinflammatory mediatorsand the deposition of A [21]. In the present review, we willhighlight our proposed concept of microglia aging, whichrefers to the fact that microglia are the potent acceleratorsof brain aging due to their induction of cognitive decline.We will also discuss the benefits of nutrients in preventingmicroglia aging and cognitive decline.

    2. The Risk of Systemic InflammatoryDiseases for AD

    RA is a chronic inflammatory bone disorder, which causesjoint damage. A postmortem survey found that the preva-lence of AD was reduced in RA patients who were long-term users of nonsteroidal anti-inflammatory agents [2225].More recently, patients with midlife RA were confirmed tohave an increased risk of cognitive impairment, over a 21-year follow-up study, in several case-control andhospital- andregister-based studies that were performed to examine theassociation between RA/arthritis and dementia/AD [26].

    Periodontitis is a chronic inflammatory disorder in theperiodontal tissues.There is growing clinical evidence to sup-port a close link between periodontitis and the developmentand progression of AD [27, 28]. More recently, the threemajor periodontal bacteria, Red complex, including Tre-ponema denticola, Tannerella forsythia, and Porphyromonasgingivalis, and their components have been detected in thebrain of AD patients [29, 30]. More details have beenreviewed by us recently [20].

    IBD is a chronic inflammatory disorder in the gut.The gutbacteria are important for inducing systemic inflammation,and LPS is a potentially associated mediator which migratesinto the intestinal capillaries [31]. Indeed, elevated LPSconcentrations can be found in the plasma of AD patients[3234], which supports a possible role of LPS in the pro-motion of neuroinflammation, and the triggering cognitivedecline [3537]. Furthermore, the chronically inflamed gutgenerates systemic proinflammatory cytokines to promoteneuroinflammation, which causes cognitive decline [38, 39].

    3. Oxidative Damage in SystemicInflammatory Diseases and AD

    3.1. Oxidative Damage in the Chronic Inflammatory Disorders.ROS contribute to the progression of chronic inflammatorybone disorders, including RA and periodontitis. The inflam-matory cell-mediated overproduction of TNF- is thought tobe the main contributor to the increased release of ROS inRA patients [40], because TNF- not only causes cell damagebut also inhibits antioxidants, such as superoxide dismutase 1(SOD1) and SOD3 [41, 42]. Numerous studies have indicatedexcess ROS levels and the depletion of antioxidant levelsin the gingival crevicular fluid [43, 44]. There is furtherevidence of higher levels of lipid peroxidation, hydrogenperoxides, and oxidative DNA damage in animal models of

    periodontitis [45]. Indeed, periodontitis is associated withsystemic oxidative stress and a reduced global antioxidantcapacity, which suggests that oxidative stress in patientswith periodontitis could be closely linked to the biomarkerof inflammation, including C-reactive protein [46]. It isconsidered that ROS are involved in the chronic inflam-matory bone disorders by regulating osteoblasts and osteo-clasts [47], because the increasedmitochondria-derived ROS,especially H

    2O2, reduces the differentiation and maturation

    of osteoblasts by inhibiting type 1 collagen and alkalinephosphatase, colony-forming unit-osteoprogenitor forma-tion, and Runt-related transcription factor 2 activation [48,49]. On the other hand, the increased ROS enhance theosteoclast numbers and resorption by stimulating receptoractivator of NF-B ligand and TNF- expression throughextracellular-signal-regulated kinase and NF-B activation[50].

    ROS are increased in the colonic mucosa of patientswith the alterations in the mucosal antioxidant defenses inIBD patients [51, 52], because the bodys major antioxidant,glutathione, is depleted but its oxidized form, glutathionedisulfide, is increased in individuals with active IBD [53, 54].The imbalance caused by the increase of ROS productionand the decrease of antioxidant capacity-induced oxidativestress is considered to be themajor pathogenic mechanism ofIBD [55, 56]. Excessive levels of ROS result in damage to thecytoskeleton protein, including the temporal disruption ofthe barrier integrity and increasing gut permeability [57, 58].Therefore, ROS promote oxidative damage, modulate theintra- and extracellular redox status, and interfere with theactivation of proteolytic enzymes in the systemic inflamma-tory environment.

    3.2. Oxidative Damage in AD. Oxidative stress is consideredto be the main cause of AD. In microglia, mitochondrialdysfunction leads to the excess production of ROS, whichpromotes the redox imbalance and stimulates proinflamma-tory gene transcription and the release of cytokines, suchas IL-1, IL-6, and TNF-, thereby inducing neuroinflam-mation. The neuroinflammation-prolonged oxidative stressleads to the accumulation of A and tau phosphorylationand then induces neurotoxicity in AD patien


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